Indole derivatives for the treatment of depression and anxiety

ABSTRACT

The present invention provides compounds of formula (I): which are useful for treating depression, anxiety, and alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine.

This application claims the benefit of Patent Cooperation TreatyApplication No. PCT/US00/32430, filed 6 Dec. 2000, and U.S. patentapplication Ser. No. 60/172,748, filed 20 Dec. 1999, the contents ofwhich are herein incorporated by reference.

Pharmaceutical researchers have discovered that the neurons of the brainwhich contain monoamines are of extreme importance in a great manyphysiological processes which very strongly affect many psychologicaland personality-affecting processes as well. In particular, serotonin(5-hydroxytryptamine; 5-HT) has been found to be a key to a very largenumber of processes which affect both physiological and psychologicalfunctions. Drugs which influence the function of serotonin in the brainare accordingly of great importance and are now used for a surprisinglylarge number of different therapies.

The early generations of serotonin-affecting drugs tended to have avariety of different physiological functions, considered from both themechanistic and therapeutic points of view. For example, many of thetricyclic antidepressant drugs are now known to be active as inhibitorsof serotonin reuptake, and also to have anticholinergic, antihistaminicor anti-α-adrenergic activity. More recently, it has become possible tostudy the function of drugs at individual receptors in vitro or ex vivo,and it has also been realized that therapeutic agents free of extraneousmechanisms of action are advantageous to the patient.

The present invention provides compounds which have highly selectiveactivity as antagonists and partial agonists of the serotonin 1_(A)receptor and a second activity as inhibitors of reuptake of serotonin.The best-known pharmaceutical with the latter efficacy is fluoxetine,and the importance of its use in the treatment of depression and otherconditions is extremely well documented and publicized. Artigas, TIPS,14, 262 (1993), have suggested that the efficacy of a reuptake inhibitormay be decreased by the activation of serotonin 1_(A) receptors with theresultant reduction in the firing rate of serotonin neurons.Accordingly, present research in the central nervous system is focusingon the effect of combining reuptake inhibitors with compounds whichaffect the 5-HT_(1A) receptor.

Compounds exhibiting both serotonin reuptake inhibition activity and5-HT_(1A) antagonist activity have been described, for example in U.S.Pat. No. 5,576,321, issued Nov. 19, 1996. It has been found thatcompounds of the present invention are potent serotonin reuptakeinhibitors and antagonists of the 5-HT_(1A) receptor.

The present invention provides compounds of formula I:

wherein

-   A is hydrogen or OH:-   B is selected from the group consisting of:

-   represents a single or a double bond;-   X is hydrogen, OH or C₁–C₆ alkoxy when    represents a single bond in the piperidine ring, and X is nothing    when    represents a double bond in the piperidine ring;-   R¹ is hydrogen, F, C₁–C₂₀ alkyl, —C(═O)NR⁸R⁹, or CN;-   R² is hydrogen, F, Cl, Br, I, OH, C₁–C₆ alkyl or C₁–C₆ alkoxy;-   R³ and R⁴ are each independently hydrogen or C₁–C₄ alkyl;-   R⁵ and R⁶ are each independently hydrogen, F, Cl, Br, I, OH, C₁–C₆    alkyl, C₁–C₆ alkoxy, halo(C₁–C₆)alkyl, phenyl, —C(═O)NR⁸R⁹, NO₂,    NH₂, CN, or phenyl substituted with from 1 to 3 substituents    selected from the group consisting of F, Cl, Br, I, OH, C₁–C₆ alkyl,    C₁–C₆ alkoxy, halo(C₁–C₆)alkyl, NO₂, NH₂, CN, and phenyl;-   R⁷ is hydrogen, F, Cl, Br, I, OH, C₁–C₆ alkyl or (C₁–C₆ alkyl)NR⁸R⁹;-   R⁸ and R⁹ are each independently hydrogen or C₁–C₁₀ alkyl;-   m is 0, 1, or 2;-   n is 0, 1, or 2;-   p is 0, 1, 2, 3 or 4; and-   q is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof;-   with the proviso that if both R³ and R⁴ represent hydrogen, then R¹    is F, C₁–C₂₀ alkyl, —C(═O)NR⁸R⁹, or CN.

The present invention further provides a method of inhibiting thereuptake of serotonin and antagonizing the 5-HT_(1A) receptor whichcomprises administering to a patient an effective amount of a compoundof formula I.

More particularly, the present invention provides a method foralleviating the symptoms caused by withdrawal or partial withdrawal fromthe use of tobacco or of nicotine; a method of treating anxiety; and amethod of treating a condition chosen from the group consisting ofdepression, hypertension, cognitive disorders, Alzheimer's disease,psychosis, sleep disorders, gastric motility disorders, sexualdysfunction, brain trauma, memory loss, eating disorders and obesity,substance abuse, obsessive-compulsive disease, panic disorder, andmigraine; which methods comprise administering to a patient an effectiveamount of a compound of formula I.

In addition, the present invention provides a method of potentiating theaction of a serotonin reuptake inhibitor comprising administering to apatient an effective amount of a compound of formula I in combinationwith an effective amount of a serotonin reuptake inhibitor.

In addition, the invention provides pharmaceutical compositions ofcompounds of formula I, including the hydrates thereof, comprising, asan active ingredient, a compound of formula I in combination with apharmaceutically acceptable carrier, diluent or excipient. Thisinvention also encompasses novel intermediates, and processes for thesynthesis of the compounds of formula I.

According to another aspect, the present invention provides the use of acompound of formula I, or a pharmaceutically acceptable salt thereof asdefined hereinabove for the manufacture of a medicament for inhibitingthe reuptake of serotonin and antagonizing the 5-HT_(1A) receptor.

According to yet another aspect, the present invention provides the useof a compound of formula I or a pharmaceutically acceptable salt thereofas defined hereinabove for inhibiting the reuptake of serotonin andantagonizing the 5-HT_(1A) receptor.

In addition, compounds of the present invention can be inhibitors ofserotonin reuptake, dopamine reuptake, and norepinephrine reuptake.

It is understood that the compounds of formula Ia:

are included within the scope of the present invention wherein thesubstituents are defined as herein.

It is further understood that the compounds of formula Iaa:

are included within the scope of the present invention wherein thesubstituents are defined as herein.

As used herein, the terms “Me”, “Et”, “Pr”, “i-Pr”, “Bu” and “t-Bu”refer to methyl, ethyl, propyl, isopropyl, butyl and tert-butylrespectively.

As used herein, the terms “Halo”, “Halide” or “Hal” refer to a chlorine,bromine, iodine or fluorine atom, unless otherwise specified herein.

As used herein the term “C₁–C₄ alkyl” refers to a straight or branched,monovalent, saturated aliphatic chain of 1 to 4 carbon atoms andincludes, but is not limited to methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl and the like.

As used herein the term “C₁–C₆ alkyl” refers to a straight or branched,monovalent, saturated aliphatic chain of 1 to 6 carbon atoms andincludes, but is not limited to methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.

As used herein the term “C₁–C₁₀ alkyl” refers to a straight or branched,monovalent, saturated aliphatic chain of 1 to 10 carbon atoms andincludes, but is not limited to methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl,2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl,octyl, 4-methyl-3-heptyl and the like.

As used herein the term “C₁–C₂₀ alkyl” refers to a straight or branched,monovalent, saturated aliphatic chain of 1 to 20 carbon atoms andincludes, but is not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 3-methylpentyl,2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl,n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl,n-nonadecyl, n-eicosyl and the like.

As used herein the term “halo(C₁–C₆)alkyl” refers to a straight orbranched alkyl chain having from one to six carbon atoms with 1, 2 or 3halogen atoms attached to it. Typical halo(C₁–C₆)alkyl groups includechloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl,2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl andthe like. The term “halo(C₁–C₆)alkyl” includes within its definition theterm “halo(C₁–C₄)alkyl”.

As used herein the term “C₁–C₆ alkoxy” refers to a straight or branchedalkyl chain having from one to six carbon atoms attached to an oxygenatom. Typical C₁–C₆ alkoxy groups include methoxy, ethoxy, propoxy,isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term “C₁–C₆alkoxy” includes within its definition the term “C₁–C₄ alkoxy”.

The designation “

” refers to a bond that protrudes forward out of the plane of the page.

The designation “

” refers to a bond that protrudes backward out of the plane of the page.

This invention includes the hydrates and the pharmaceutically acceptablesalts of the compounds of formula I. A compound of this invention canpossess a sufficiently basic functional group which can react with anyof a number of inorganic and organic acids, to form a pharmaceuticallyacceptable salt.

The term “pharmaceutically acceptable salt” as used herein, refers tosalts of the compounds of formula I which are substantially non-toxic toliving organisms. Typical pharmaceutically acceptable salts includethose salts prepared by reaction of the compounds of the presentinvention with a pharmaceutically acceptable mineral or organic acid.Such salts are also known as acid addition salts. Such salts include thepharmaceutically acceptable salts listed in Journal of PharmaceuticalScience, 66, 2–19 (1977) which are known to the skilled artisan.

Acids commonly employed to form acid addition salts are inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalicacid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citricacid, benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide,acetate, propionate, decanoate, caprate, caprylate, acrylate, ascorbate,formate, hydrochloride, dihydrochloride, isobutyrate, caproate,heptanoate, propiolate, propionate, phenylpropionate, salicylate,oxalate, malonate, succinate, suberate, sebacate, fumarate, malate,maleate, hydroxymaleate, mandelate, nicotinate, isonicotinate,cinnamate, hippurate, nitrate, phthalate, teraphthalate,butyne-1,4-dioate, butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate,naphthalene-2-benzoate, phthalate, p-toluenesulfonate,p-bromobenzenesulfonate, p-chlorobenzenesulfonate, xylenesulfonate,phenylacetate, trifluoroacetate, phenylpropionate, phenylbutyrate,citrate, lactate, α-hydroxybutyrate, glycolate, tartrate,benzenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate,hydroxyethanesulfonate, naphthalene-1-sulfonate,napththalene-2-sulfonate, mandelate, tartarate, and the like. Preferredpharmaceutically acceptable acid addition salts are those formed withmineral acids such as hydrochloric acid and hydrobromic acid, and thoseformed with organic acids such as maleic acid, oxalic acid andmethanesulfonic acid.

It should be recognized that the particular counterion forming a part ofany salt of this invention is usually not of a critical nature, so longas the salt as a whole is pharmacologically acceptable and as long asthe counterion does not contribute undesired qualities to the salt as awhole. It is further understood that such salts may exist as a hydrate.

As used herein, the term “stereoisomer” refers to a compound made up ofthe same atoms bonded by the same bonds but having differentthree-dimensional structures which are not interchangeable. Thethree-dimensional structures are called configurations. As used herein,the term “enantiomer” refers to two stereoisomers whose molecules arenonsuperimposable mirror images of one another. The term “chiral center”refers to a carbon atom to which four different groups are attached. Asused herein, the term “diastereomers” refers to stereoisomers which arenot enantiomers. In addition, two diastereomers which have a differentconfiguration at only one chiral center are referred to herein as“epimers”. The terms “racemate”, “racemic mixture” or “racemicmodification” refer to a mixture of equal parts of enantiomers.

The term “enantiomeric enrichment” as used herein refers to the increasein the amount of one enantiomer as compared to the other. A convenientmethod of expressing the enantiomeric enrichment achieved is the conceptof enantiomeric excess, or “ee”, which is found using the followingequation:

${ee} = {\frac{E^{1} - E^{2}}{E^{1} + E^{2}} \times 100}$wherein E¹ is the amount of the first enantiomer and E² is the amount ofthe second enantiomer. Thus, if the initial ratio of the two enantiomersis 50:50, such as is present in a racemic mixture, and an enantiomericenrichment sufficient to produce a final ratio of 50:30 is achieved, theee with respect to the first enantiomer is 25%. However, if the finalratio is 90:10, the ee with respect to the first enantiomer is 80%. Anee of greater than 90% is preferred, an ee of greater than 95% is mostpreferred and an ee of greater than 99% is most especially preferred.Enantiomeric enrichment is readily determined by one of ordinary skillin the art using standard techniques and procedures, such as gas or highperformance liquid chromatography with a chiral column. Choice of theappropriate chiral column, eluent and conditions necessary to effectseparation of the enantiomeric pair is well within the knowledge of oneof ordinary skill in the art. In addition, the enantiomers of compoundsof formulas I or Ia can be resolved by one of ordinary skill in the artusing standard techniques well known in the art, such as those describedby J. Jacques, et al., “Enantiomers, Racemates, and Resolutions”, JohnWiley and Sons, Inc., 1981.

Some of the compounds of the present invention have one or more chiralcenters and may exist in a variety of stereoisomeric configurations. Asa consequence of these chiral centers, the compounds of the presentinvention occur as racemates, mixtures of enantiomers and as individualenantiomers, as well as diastereomers and mixtures of diastereomers. Allsuch racemates, enantiomers, and diastereomers are within the scope ofthe present invention.

The terms “R” and “S” are used herein as commonly used in organicchemistry to denote specific configuration of a chiral center. The term“R” (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term“S” (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon their atomic number (in order ofdecreasing atomic number). A partial list of priorities and a discussionof stereochemistry is contained in “Nomenclature of Organic Compounds:Principles and Practice”, (J. H. Fletcher, et al., eds., 1974) at pages103–120.

The specific stereoisomers and enantiomers of compounds of formula (I)can be prepared by one of ordinary skill in the art utilizing well knowntechniques and processes, such as those disclosed by Eliel and Wilen,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., 1994,Chapter 7, Separation of Stereoisomers. Resolution. Racemization, and byCollet and Wilen, “Enantiomers, Racemates, and Resolutions”, John Wiley& Sons, Inc., 1981. For example, the specific stereoisomers andenantiomers can be prepared by stereospecific syntheses usingenantiomerically and geometrically pure, or enantiomerically orgeometrically enriched starting materials. In addition, the specificstereoisomers and enantiomers can be resolved and recovered bytechniques such as chromatography on chiral stationary phases, enzymaticresolution or fractional recrystallization of addition salts formed byreagents used for that purpose.

As used herein, the term “SRI” refers to serotonin reuptake inhibitor.

As used herein the term “serotonin” is equivalent to and interchangeablewith the terms “5-HT” or “5-hydroxytryptamine”.

As used herein, “Pg” refers to a protecting group on the amine which iscommonly employed to block or protect the amine while reacting otherfunctional groups on the compound. Examples of protecting groups (Pg)used to protect the amino group and their preparation are disclosed byT. W. Greene, “Protective Groups in Organic Synthesis,” John Wiley &Sons, 1981, pages 218–287. Choice of the protecting group used willdepend upon the substituent to be protected and the conditions that willbe employed in subsequent reaction steps wherein protection is required,and is well within the knowledge of one of ordinary skill in the art.Preferred protecting groups are t-butoxycarbonyl also known as a BOCprotecting group, and benzyloxycarbonyl also known as a Cbz protectinggroup.

The compounds of formula I can be prepared by techniques and proceduresreadily available to one of ordinary skill in the art. For example,various starting materials and general procedures which may be employedby one of ordinary skill in the art in the preparation of compounds offormula I are described in U.S. Pat. No. 3,929,793, issued Dec. 30,1975, U.S. Pat. No. 4,304,915, issued Dec. 8, 1981, U.S. Pat. No.4,288,442, issued Sep. 8, 1981, U.S. Pat. No. 4,361,562, issued Nov. 30,1982, U.S. Pat. No. 4,460,586, issued Jul. 17, 1984, U.S. Pat. No.4,704,390, issued Nov. 3, 1987, U.S. Pat. No. 4,935,414, issued Jun. 19,1990, U.S. Pat. No. 5,013,761, issued May 7, 1991, and U.S. Pat. No.5,614,523, issued Mar. 25, 1997. More specifically, compounds of formulaI can be prepared by following the procedures as set forth in Schemes Ithrough IV. All substituents, unless otherwise indicated, are previouslydefined. The reagents and starting materials are readily available toone of ordinary skill in the art. More specifically, Schemes I throughII provide general syntheses of various intermediate piperidines.

In Scheme I, step A, compound (1) is added to piperidone (2) underconditions well known in the art, to provide the alcohol (3). Forexample, an appropriately substituted naphthalene, such as2-bromonaphthalene, 1-bromo-5-methoxy-naphthalene,2-bromo-7-methoxy-naphthalene, 6-iodo-1-methoxy-naphthalene, and thelike, is dissolved in a suitable organic solvent, such astetrahydrofuran, and cooled to about −78° C. To this stirring solutionis added an excess of a suitable base, such as t-butyllithium. Themixture is stirred for about 1 to 3 hours, and about 1.0 to about 1.1equivalents of the piperidone (2) are added. The reaction is allowed towarm to room temperature and the alcohol (3) is isolated and purified bytechniques well known in the art. For example, the mixture is dilutedwith water and extracted with a suitable organic solvent, such as ethylacetate. The organic extracts are combined, washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The crude alcohol can then be purified by flash chromatography on silicagel with a suitable eluent, such as ethyl acetate/hexanes to provide thepurified alcohol (3). Alternatively, the crude isolated alcohol (3) canbe carried directly onto the next step.

The piperidones (2) are readily available to one of ordinary skill inthe art utilizing known starting materials. For example, I. V. Micovic,et al., J. Chem. Soc., Perkin Trans., 1(16), 2041–2050 (1996) teach thepreparation of variously substituted piperidine-2,4-diones. Suchpiperidine-2,4-diones can be selectively protected, alkylated, andreduced under conditions well known in the art to provide the desiredpiperidone (2). For example, compounds of the formula (2a′)

can be prepared in a manner analogous to the procedure described byMicovic et al. Above, which can then be reduced to provide the2,2-disubstituted-N-protected-4-piperidone (2a″).

In Scheme I, step B, the alcohol (3) is dehydrated under standardconditions to provide the 1,2,5,6-tetrahydropyridine (4) wherein Pg′ ismaintained as a protecting group and does not represent hydrogen. Forexample, the alcohol (3) is dissolved in a suitable organic solvent,such as toluene, and treated with an excess of a suitable acid, such asp-toluenesulfonic acid monohydrate. The reaction mixture is heated atreflux for about 6 to 12 hours and then cooled. The1,2,5,6-tetrahydropyridine is then isolated and purified underconditions well known in the art. For example, the cooled reactionmixture is basified with 2 N sodium hydroxide and extracted with asuitable organic solvent, such as ethyl acetate. The organic extractsare combined, washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The crude residue is thenpurified by flash chromatography on silica gel with a suitable eluent,such as methanol/methylene chloride to provide the purified1,2,5,6-tetrahydropyridine (4).

Alternatively, in Scheme I, step B, the alcohol (3) can be dehydratedand deprotected concomitantly under standard conditions to provide thecompound (4) wherein Pg′ is hydrogen. For example, the alcohol (3)wherein the protecting group is N-t-butoxycarbonyl is dissolved in asuitable organic solvent, such as dry dichloromethane, and the solutionis cooled to about 0° C. To this solution is added excesstrifluoroacetic acid and the reaction mixture is stirred at about 0° C.for about 15 h. The reaction is then quenched at room temperature withsaturated aqueous NaHCO₃ solution. The product is then isolated bytechniques well known in the art, such as extraction and then purifiedby flash chromatography. For example, the mixture is extracted with asuitable organic solvent, such as dichloromethane, the combined organicextracts are dried over anhydrous magnesium sulfate, filtered andconcentrated under vacuum to provide the crude compound (4). Thismaterial can be purified by flash chromatography on silica gel with asuitable eluent, such as ethyl acetate/hexanes.

In Scheme I, step C, the 1,2,5,6-tetrahydropyridine (4) is hydrogenatedunder conditions well known in the art to provide a mixture ofpiperidines (5a) and (5b). For example, the 1,2,5,6-tetrahydropyridine(4) is dissolved in a suitable organic solvent, such as ethanol andtreated with a suitable catalyst, such as 5% palladium on carbon. Themixture is then placed under an atmosphere of hydrogen and stirred forabout 12 hours at room temperature. The reaction mixture is thenfiltered to remove the catalyst and the filtrate is concentrated undervacuum to provide a mixture of isomers (5a) and (5b). It is readilyappreciated by one of ordinary skill in the art that various isomers mayexist at this step wherein the R groups (R³ and R⁴) can be either cis ortrans to the naphthyl group. It is further recognized that these isomersmay be separated from one another by techniques well known in the art,such as flash chromatography, radial chromatography or high performanceliquid chromatography on silica gel with a suitable eluent, such asmethanol/methylene chloride. Alternatively, the mixture of isomers maybe carried on to the next step or the separated isomers may individuallybe carried onto the next step.

In Scheme I, step D, wherein Pg′ is a protecting group and not hydrogen,the piperidines (5a) and (5b) are deprotected under conditions wellknown to one of ordinary skill in the art to provide piperidines (6a)and (6b). For example, when Pg is a methyl group, the piperidines (5a)and (5b) are dissolved in a suitable organic solvent, such asdichloroethane and cooled to about 0° C. The cooled solution is thentreated with an excess of 1-chloroethylchloroformate. The reaction isthen allowed to warm to room temperature and then heated at reflux forabout 12 hours. After cooling, the solvent is then removed under vacuumand the residue is dissolved in a suitable organic solvent, such asmethanol. The solution is then heated at reflux for about 2 to 4 hours,cooled to room temperature, and then concentrated under vacuum. Theresidue is treated with water and a suitable organic solvent, such asethyl acetate. The phases are separated and the aqueous phase isextracted with ethyl acetate. The organic extracts, including the firstorganic phase, are combined, rinsed with brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum to provide thecrude piperidines (6a) and (6b). The mixture can then be separated intopurified individual stereoisomers if they were not already separated instep C using similar techniques, such as flash chromatography, radialchromatography or high performance chromatography on silica gel with asuitable eluent, such as methanol/methylene chloride.

It is readily appreciated by one of ordinary skill in the art that thesequence of steps of dehydration, deprotection, and reduction can bevaried depending upon the protecting groups utilized and the ultimateproducts desired. The conditions required for varying the sequence arewell within the knowledge of one of ordinary skill in the art.

In Scheme IA, the steps A through D are carried out in a manneranalogous to the procedures set forth in Scheme I, steps A through Drespectively.

In Scheme IAA, the steps A through D are carried out in a manneranalogous to the procedures set forth in Scheme I, steps A through Drespectively.

In Scheme IB, alcohol (3a) is alkylated under standard conditions toprovide the ether (3b). For example, alcohol (3a), wherein theprotecting group is N-t-butoxycarbonyl, is dissolved in a suitableorganic solvent, such as dry MeOH and the solution is cooled to about 0°C. To this solution is added excess trifluoroacetic acid. The reactionmixture is then stirred at room temperature for about one to 6 days. Thereaction is then quenched at room temperature with saturated aqueousNaHCO₃ solution, extracted with a suitable organic solvent such asdichloromethane, the combined organic extracts are dried over anhydrousmagnesium sulfate, filtered and concentrated under vacuum to provide thecrude ether (3b). The crude ether (3b) can then be purified by flashchromatography on silica gel with a suitable eluent, such as 7% (10%conc. NH₄OH in MeOH)/CH₂Cl₂.

In Scheme IC, alcohol (3a) can be deprotected without dehydration understandard conditions well known in the art, through appropriate choice ofprotecting groups, to provide the deprotected alcohol (3b′). Forexample, the alcohol (3a), wherein the protecting group is a —CH₂CH═CH₂group, is dissolved in a suitable solvent, such as aqueous ethanol (10%H₂O). The solution is then treated with chlorotris(triphenylphosphine)rhodium(I) (Wilkinson's catalyst) and approximately 50% of the solventis then distilled off over a period of about 1 hour. An additional 65 mLof solvent and 45 mg of Wilkinson's catalyst is added and the reactionmixture is refluxed for about 1 hour and then the solvent is againdistilled off to about 50% volume. The reaction mixture is thenevaporated and the residue is purified using silica gel chromatographywith a suitable eluent, such as dichloromethane/20% methanol, 2%anhydrous ammonia in dichloromethane gradient, to provide the purifieddeprotected alcohol (3b′).

In Scheme II, step A, a naphthylboronic acid (7), such as2-naphthylboronic acid is combined with the 1,2,5,6-tetrahydropyridine(8) to provide the coupled compound (9). For example, about 1 to 1.5equivalents of a naphthylboronic acid (7) is combined with about 1equivalent of 1,2,5,6-tetrahydropyridine (8), about 2 equivalents oflithium chloride, a catalytic amount oftetrakis(triphenylphosphine)palladium(0) in a mixture of 2 M aqueoussodium carbonate and tetrahydrofuran. The mixture is heated at refluxfor about 12 hours and then cooled to room temperature. The reaction isthen treated with 2 N sodium hydroxide and extracted with a suitableorganic solvent, such as ethyl acetate. The organic extracts arecombined, rinsed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The crude residue is thenpurified by flash chromatography on silica gel with a suitable eluentsuch as ethyl acetate/hexanes to provide the compound (9).

In Scheme II, step B, the compound (9) is hydrogenated under standardconditions to provide the piperidines (10a) and (10b). For example, thecompound (9) is dissolved in a suitable organic solvent, such asmethanol, treated with a suitable catalyst, such as 5% palladium oncarbon and stirred under an atmosphere of hydrogen for about 12 hours atroom temperature. The reaction mixture is then filtered to remove thecatalyst and the filtrate is concentrated under vacuum to providepiperidines (10a) and (10b). As noted in Scheme I, step C, it is readilyappreciated by one of ordinary skill in the art that various isomers mayexist at this particular step wherein the R groups (R³ or R⁴) can beeither cis or trans to the naphthyl group. It is further recognized thatthese isomers may be separated from one another by techniques well knownin the art, such as flash chromatography, radial chromatography or highperformance liquid chromatography on silica gel with a suitable eluent,such as methanol/methylene chloride. Alternatively, the mixture ofisomers may be carried on to the next step or the separated isomers mayindividually be carried onto the next step.

In Scheme II, step C, the piperidines (10a) and (10b) are deprotectedunder conditions well known in the art to provide the piperidines (6a)and (6b). For example, piperidines (10a) and (10b) are dissolved in asuitable solvent mixture, such as 50% water/isopropanol and treated withan excess of a suitable base, such as potassium hydroxide. The reactionmixture is then heated at reflux for about 1 to 3 days and then cooledto room temperature. 2 N sodium hydroxide is added and the reaction isextracted with a suitable organic solvent, such as ethyl acetate. Theorganic extracts are combined, rinsed with brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The cruderesidue is then purified by flash chromatography on silica gel with asuitable eluent, such as methanol/methylene chloride to provide thepurified piperidines (6a) and (6b). The mixture can then be separatedinto individual stereoisomers if they were not already separated in stepC using similar techniques, such as flash chromatography, radialchromatography or high performance chromatography on silica gel with asuitable eluent, such as methanol/methylene chloride.

It is readily appreciated by one of ordinary skill in the art thatcompounds (4), (4′) and (9) can be deprotected prior to reduction andthe unsaturated deprotected piperidines can be used directly in SchemesIII and IV.

In Scheme IIA, step A, a 2-halo-benzothiazole (11), such as2-chloro-4-fluorobenzothiazole, is combined with the1,2,5,6-tetrahydropyridine (8), to provide the coupled compound (9′).For example, about 1 equivalent of a 2-halo-benzothiazole (11) iscombined with about 1.2 equivalents of 1,2,5,6-tetrahydropyridine (8),about 1 equivalent of bis(trimethyltin), about 3 equivalents of lithiumchloride, and a catalytic amount oftetrakis(triphenylphosphine)palladium(0) in a suitable organic solvent,such as 1,4-dioxane. The mixture is heated at reflux for about 20 hoursand then cooled to about 20° C. The reaction is then treated withsaturated potassium fluoride and ethyl acetate, and stirred for about 2hours. The organic phase is separated, washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Thecrude residue is then purified by flash chromatography on silica gelwith a suitable eluent such as ethyl acetate/hexanes to provide thecompound (9′).

In Scheme IIA, Step B, the compound (9′) is deprotected under standardconditions to provide the compound (12). For example, the compound (9′)is dissolved in a suitable organic solvent, such as dichloromethane,cooled to about 0° C. and treated with an excess of trifluoroaceticacid. The mixture is then stirred for about 30 minutes, then warmed toabout 20° C. and stirred for an additional 20 minutes. The mixture isthen diluted with 2 N sodium hydroxide and extracted with a suitableorganic solvent, such as ethyl acetate. The organic extracts arecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum to provide the crude compound (12). Compound (12) can thenbe purified by flash chromatography on silica gel with a suitableeluent, such as (dichloromethane/10% methanol 1% ammonium hydroxide indichloromethane gradient elution) to provide the purified compound (12).

In Scheme IIA, step C, the compound (12) is hydrogenated under standardconditions to provide the cis and trans isomers (6a″) and (6b″). Forexample, the compound (12) is dissolved in a suitable organic solvent,such as ethanol and treated with a catalytic amount of platinum oxide.The mixture is then hydrogenated under 1 atmosphere for about 20 hours,filtered and the filtrate concentrated under vacuum to provide the cisand trans isomers (6a″) and (6b″). The compounds can then be separatedusing standard techniques well known to one of ordinary skill in theart, such as recrystallization techniques, flash chromatography orchiral chromatography.

It is readily appreciated by one of ordinary skill in the art thatpiperidines of structure (16) [see Schemes III and IV below], wherein Brepresents:

can be prepared under standard conditions, such as in a manner analogousto the procedures set forth in Schemes I through IIA for preparation ofthe piperidines described therein.

Compounds of formula I are prepared following generally the procedureset forth in Scheme III. All substituents, unless otherwise indicated,are previously defined. The reagents and starting materials are readilyavailable to one of ordinary skill in the art.

In Scheme III, step A, the compound (13) is coupled with the compound(14) under standard conditions well known in the art, to provide thecompound (15). For example, the compound (13) is dissolved in a suitableorganic solvent, such as DMF, and treated with about one equivalent of asuitable base, such as sodium hydride. To the stirring solution is addedabout 1.1 equivalents of compound (14) and the reaction is stirred atabout −10° C. to room temperature, for about 20 minutes to about 1 hour.Compound (15) is then isolated and purified by techniques well known inthe art, such as extraction techniques and flash chromatography. Forexample, the reaction mixture is diluted with water and extracted with asuitable organic solvent, such as ethyl acetate. The organic extractsare combined, dried over anhydrous magnesium sulfate, filtered andconcentrated under vacuum to provide the crude material. The crudematerial can be purified by flash chromatography on silica gel with asuitable eluent, such as ethyl acetate/hexanes.

In Scheme III, step, B the compound (15) is coupled with the piperidine(16) under standard conditions well known in the art to provide thecompound of formula I. For example, the compound (15) is dissolved in asuitable organic solvent, such as dimethylformamide with about oneequivalent of a suitable neutralizing agent, such as sodium bicarbonate.To this mixture is added about one equivalent of a piperidine (16) andthe mixture is heated at about 70° C. to 90° C. for about 4 hours to 12hours. The compound of formula I is then isolated and purified bytechniques well known in the art, such as extraction techniques andflash chromatography. For example, the reaction mixture is diluted withwater and extracted with a suitable organic solvent, such as ethylacetate. The organic extracts are combined, washed with water and brine,dried over anhydrous magnesium sulfate, filtered and concentrated undervacuum to provide the crude material. The crude material can be purifiedby flash chromatography on silica gel with a suitable eluent, such asethyl acetate/hexanes.

Compounds of formula la are prepared following generally the procedureset forth in Scheme IV. All substituents, unless otherwise indicated,are previously defined. The reagents and starting materials are readilyavailable to one of ordinary skill in the art.

In Scheme IV, step A, the compound of structure (13) is coupled with theepoxide (17) to provide the epoxide (18). For example, compound (13) isdissolved in a suitable organic solvent, such as dimethylformamide andcooled to 0° C. About 1.1 equivalents of sodium hydride is added to thesolution which is then stirred for about one hour. A solution of oneequivalent of the epoxide (17) in dimethylformamide is then addeddropwise to the solution. The reaction mixture is then stirred for about1 to 24 hours at 0° C. It is then quenched with water. The resultingsolution is then extracted with a suitable organic solvent, such asethyl acetate. The organic layers are combined, washed with water, driedover anhydrous magnesium sulfate, filtered and concentrated to providethe crude epoxide (18). The crude product can be purified bycrystallization with a suitable solvent, such as dichloromethane or byflash chromatography on silica gel with a suitable eluent, such asdichloromethane/hexanes.

In Scheme IV, step B, the epoxide (18) is opened with the substitutedpiperidine of structure (16) under standard conditions well known in theart, such as those disclosed by Krushinski, et al. in U.S. Pat. No.5,576,321, issued Nov. 19, 1996, to provide the compound of formula la.For example, an epoxide (18), such as(S)-(+)-4-(oxiranylmethoxy)-1H-indole, is dissolved in a suitableorganic solvent, such as methanol, and treated with about one equivalentof piperidine (16). The solution is then heated at reflux for about 8 to12 hours and then cooled to room temperature. The reaction mixture isthen concentrated under vacuum and the crude residue is purified and theresulting stereoisomers separated from each other by techniques wellknown in the art, such as flash chromatography, radial chromatography orhigh performance liquid chromatography on silica gel with a suitableeluent, such as methanol/methylene chloride.

The following examples are illustrative only and represent typicalsyntheses of the compounds of formula I and formula Ia as describedgenerally above. The reagents and starting materials are readilyavailable to one of ordinary skill in the art. As used herein, thefollowing terms have the meanings indicated: “eq” or “equiv.” refers toequivalents; “Ig” refers to grams; “mg” refers to milligrams; “L” refersto liters; “mL” refers to milliliters; “μL” refers to microliters; “mol”refers to moles; “mmol” refers to millimoles; “psi” refers to pounds persquare inch; “min” refers to minutes; “h” or “hr” refers to hours; “°C.” refers to degrees Celsius; “TLC” refers to thin layerchromatography; “HPLC” refers to high performance liquid chromatography;“R_(f)” refers to retention factor; “R_(t)” refers to retention time;“δ” refers to parts per million down-field from tetramethylsilane; “THF”refers to tetrahydrofuran; “DMF” refers to N,N-dimethylformamide; “DMSO”refers to methyl sulfoxide; “LDA” refers to lithium diisopropylamide;“mp” refers to melting point; “aq” refers to aqueous; “n-BuLi” refers ton-butyllithium; “EtOAc” refers to ethyl acetate; “iPrOAc” refers toisopropyl acetate; “MeOH” refers to methanol; “EtOH” refers to ethanol;“PPA” refers to polyphosphoric acid; “MTBE” refers to tert-butyl methylether, and “RT” refers to room temperature.

Preparation 1 Preparation of 1-Bromo-5-methoxy-naphthalene

Preparation of 5-Bromo-3,4-dihydro-1(2H)-naphthalenone and7-bromo-3,4-dihydro-1(2H)-naphthalenone.

Anhydrous AlCl₃ (66.67 g, 0.50 mol, 99.99%) under N₂ was stirredvigorously as 1-tetralone (29.83 g, 0.20 mol) was added dropwise over ˜7min. The evolved HCl gas was scrubbed through 5 N NaOH. The resultingmixture was a dark brown oil that exothermed to 75° C. When thetemperature had cooled to 50° C., Br₂ was added dropwise over 15 min.The mixture, which had cooled further to 40° C., was heated to 80° C.for 5 min, then poured into a mixture of ice (600 g) and 12 N HCl (80mL). All the ice melted, leaving a cool dark mixture which was dilutedwith H₂O (200 mL) and extracted with CH₂Cl₂ (200 mL, 100 mL). Thecombined extracts were dried with MgSO₄ and concentrated in vacuo(30–60° C.) to a dark brown oil (45.6 g; theory=45.02 g).

Chromatography over silica gel 60 with 8:1 heptane:THF did not proveeffective, but two passes through the Biotage™ radially pressured silicagel cartridges using 9:1 heptane:MTBE as eluent produced acceptably purefractions.

5-Bromo-3,4-dihydro-1(2H)-naphthalenone was isolated as an orange oil(12.27 g, 28.3%). HPLC showed an apparent wide divergence in absorbancesat 230 nm for the two regioisomers, and was therefore not reliable for apotency check. TLC on silica gel (4:1 heptane:MTBE) confirmed modestcontamination with 7-bromo-3,4-dihydro-1(2H)-naphthalenone.

7-Bromo-3,4-dihydro-1(2H)-naphthalenone was isolated as ayellowish-white solid (15.48 g, 35.8%); mp 69.5–75° C. (lit 74–75° C.).¹H NMR (CDCl₃) corresponded to the literature description, plus a traceof heptane and an undefined by-product. TLC showed it to be cleaner than5-bromo-3,4-dihydro-1(2H)-naphthalenone.

A third fraction of orange oil (9.06 g, 20.9%) was isolated. TLC showedit to be a nearly 1:1 ratio of 5-bromo-3,4-dihydro-1(2H)-naphthalenone,and 7-bromo-3,4-dihydro-1(2H)-naphthalenone.

Preparation of 2,5-Dibromo-3,4-dihydro-1(2H)-naphthalenone.

A clear yellow solution of 5-bromo-3,4-dihydro-1(2H)-naphthalenone(12.09g, 53.7 mmol) in freshly opened Et₂O (220 mL) under an N₂ atmosphere waschilled to −5° C. HCl was bubbled in subsurface for 1 min, causing novisible change. The dropwise addition of a solution of Br₂ (8.58 g, 53.7mmol) in CH₂Cl₂ (20 mL) and Et₂O (2 mL) to the vigorously stirringsolution of 5-bromo-3,4-dihydro-1(2H)-naphthalenone over 2 h (each dropwas allowed to fully decolorize before adding the next) produced aproduct mixture that assayed by HPLC. Peak area showed 79.4% titlecompound, 9.5% unreacted 5-bromo-3,4-dihydro-1(2H)-naphthalenone, 0.6%unidentified, and 9.4% 2,2′,5-tribromo-1-tetralone. The addition of H₂Oproduced a top light brown organic phase, and a clear, colorless bottomaqueous phase which was separated. After drying with MgSO₄, the organiclayer was concentrated in vacuo at room temperature to give the crudeintermediate title compound as a light brown oil (16.08 g, 98.5%).

Preparation of 5-Bromo-1-naphthalenol.

The crude mixture of 2,5-dibromo-1-tetralone (16.08 g, 52.9 mmol,), LiCl(5.61 g, 132 mmol), and 120 mL of dry DMF were combined under an N₂atmosphere and heated to reflux (˜155° C.). The mixture turned darkbrown. HPLC showed complete consumption of the starting material in just0.5 h. After cooling to room temperature, the mixture was diluted with 1N HCl (200 mL) and extracted three times with Et₂O (100 mL, 25 mL, 25mL). The Et₂O layers were combined to give a brown hazy mixture (someemulsion). After stirring with decolorizing carbon (10 g, Calgon ADP)and filtration through hyflo supercel, a clear light yellow solution wasobtained. This solution was extracted with 3 N NaOH (100 mL, 25 mL),leaving the non-naphtholic byproducts behind. The brown NaOH extractswere combined, acidified to pH 1 with conc. HCl, and extracted withCH₂Cl₂ (100 mL, 25 mL). The combined CH₂Cl₂ layers formed a deep redsolution. After stirring with decolorizing carbon (5 g, Darco G-60) andfiltration through hyflo supercel, the solution was again light yellow.An equal volume of heptane was added, and the CH₂Cl₂ was distilled away.When the temperature reached 75° C., gray precipitate became evident.This increased substantially on cooling to room temperature. Followingfiltration and drying in vacuo at 50° C., a product mixture of graysolid (5.92 g, 50.2%) was obtained. HPLC showed this to be a mixture of7-bromo-1-naphthol (48.3%) and 5-bromo-1-naphthol (50.8%). However, ¹HNMR (CDCl₃) integration showed that the actual ratio was about 9/15-Br/7-Br. Preparative reverse phase HPLC gave one peak of5-bromo-1-naphthol as a white solid (3.22 g, 27.3%).

Preparation of Final Title Compound.

Purified 5-bromo-1-naphthol (3.22 g, 14.4 mmol), was dissolved in CH₃CN(50 mL), giving a clear and nearly colorless solution. Dimethylsulfate(2.72 g, 21.6 mmol, 1.5 equiv), K₂CO₃ (3.0 g, 21.6 mmol), andtetrabutylammonium bromide (TBAB, 20 mg) as phase transfer catalyst wereadded, and the resulting mixture was stirred for 16 h. HPLC revealed nodetectable starting material, when H₂O (50 mL) was added. The inorganicsalt promptly dissolved, followed immediately by crystallization of theproduct. Following filtration, an H₂O wash (50 mL) of the cake, anddrying in vacuo at 50° C., provided the final title compound as a lighttan crystalline solid (3.07 g, 90.0%): mp 68.5–69.5° C. Satisfactoryelemental analysis was obtained when block dried at 60° C. HPLC of99.6%.

Preparation 2 Preparation of 2-Bromo-7-methoxy-naphthalene

Preparation of 7-Bromo-2-naphthalenol.

Triphenyl phosphine (89.7 g, 0.342 mol) and acetonitrile (350 mL) werecombined in a 1-L flask under N₂ atmosphere. The mixture was cooled to10° C. Bromine (17.6 mL, 0.342 mol) was added dropwise over 10 minutes.The cooling bath was removed and 2,7-dihydroxynaphthalene (50.0 g, 0.312mol) was added along with 350 mL of CH₃CN rinse. The resulting yellowtan mixture was heated at reflux for 3 hours. Acetonitrile was distilledoff under a water aspirator pressure over 2 hours, resulting in agrayish white solid. The solid was heated to 280° C. over 30 minutesgiving a black liquid. The liquid was heated to 310° C. over 20 minutesand the temperature was maintained at 310° C. for an additional 15minutes until gas evolution ceased. The black mixture was cooled to roomtemperature. Chromatography yielded 34.5 g of the intermediate titlecompound as an off-white solid which was 87% pure by HPLC (43% yield).

Preparation of Final Title Compound.

2-Bromo-7-hydroxynaphthalene (34.1 g, 0.134 mol), DMF (290 mL) andpowdered potassium carbonate (31.8 g, 0.230 mol) were combined in a500-mL flask under N₂ atmosphere. Methyl iodide (14.3 mL, 0.230 mol) wasadded at once and the dark yellow mixture was stirred vigorously at roomtemperature for 3 ¾ hours. Water (290 mL) was added dropwise over 15minutes to induce crystallization. The mixture was stirred at roomtemperature for 1 hour. The product was filtered off and washed with 200mL of a 1:1 mixture of DMF and water. The solid was dried in vacuo at50° C. to yield 32.6 g of pale yellow solid (HPLC: 89%). The solid wasdissolved in 300 mL of boiling MeOH. The hot solution was filtered, thenplaced in a freezer overnight. The resulting crystals were filtered andwashed with 100 mL of cold MeOH. The solid was dried in vacuo at 50° C.to give 27.0 g of pale yellow solid (HPLC: 95%). The solid was dissolvedin 100 mL of boiling i-PrOH then allowed to cool to room temperature.The resulting solid was filtered and washed with 100 mL of i-PrOH. Thesolid was dried in vacuo at 50° C. to yield 22.8 g of final titlecompound as pale yellow crystals.

Preparation 3 Preparation of 6-Iodo-1-methoxy-naphthalene

Preparation of 5-Bromo-2-naphthalenecarboxylic acid.

2-Naphthoic acid (50;0 g, 0.290 mol), glacial acetic acid (250 mL),bromine (15 mL, 0.291 mol) and iodine (1.3 g, 0.005 mol) were combinedin a flask under N₂ atmosphere. The mixture was heated at reflux for 35minutes then cooled to room temperature. The thick yellow mixture wasstirred at room temperature for 1 hour. The mixture was filtered and thepale orange solid was rinsed with ˜100 mL of the filtrate. The solid wasdried in vacuo at 55° C. overnight to yield 55.5 g of pale orange solid.The solid was slurried in 275 mL of 1 N NaOH for 30 minutes. The solidwas filtered off and rinsed 3 times with 50 mL portions of the filtrate.The solid was air dried in the hood over the weekend to yield 46.7 g ofsolid. The solid was added to 220 mL of water. Concentrated HCl (15 mL)was added to obtain pH of 1.3 and the mixture was stirred for 4 hours.The solid was filtered off and washed with 200 mL of water. The solidwas dried in vacuo at 50° C. to give 37.6 g of intermediate titlecompound as white crystals (HPLC: 90% with 9% 2-naphthoic acid, 46%yield).

Preparation of 5-Bromo-2-naphthalenecarboxylic acid, Methyl Ester.

5-Bromo-2-naphthoic acid (17.33 g, 69 mmol) and 250 mL of MeOH werecombined in a flask under N₂ atmosphere. Thionyl chloride (5.84 mL, 80mmol) was added dropwise over 15 minutes at a temperature of 25–30° C.,resulting in a pale yellow mixture. The mixture was heated at reflux for3 ¼ hours. The resulting yellow solution was concentrated in vacuo to137.4 g of solution then placed in a freezer overnight. The resultingthick mixture was filtered and the solid was washed with 100 mL of coldMeOH. The solid was dried in vacuo at 50° C. to give 11.39 g of theintermediate title compound as white crystals. A second crop wasfiltered and washed with 100 mL of cold MeOH. The solid was dried to1.31 g of white crystals. Yield: 69%, 2 crops.

Preparation of 5-Methoxy-2-naphthoic acid.

A 25% solution of sodium methoxide in MeOH (63 mL, 0.258 mol) was addedto a 500-mL flask under N₂ atmosphere. Cupric iodide (recrystallized,4.19 g, 22 mmol), 160 mL of pyridine, 160 mL of MeOH and methyl5-bromo-2-naphthoate (11.39 g, 43 mmol) were added to the flask to givea yellow green mixture. The mixture was heated at reflux for 30 hours.The mixture was cooled to room temperature and water (850 mL) was addedresulting in a rust colored mixture with pH of 12.8. The pH was adjustedto 1.0 by addition of concentrated HCl, resulting in a whiteprecipitate. The mixture was cooled to 10° C., filtered, and the solidwas washed with cold water. The solid was dried to 11.03 g whitecrystals. The solid was taken up in 200 mL of EtOAc and 150 mL of water.The pH of the mixture was 3.5. The pH was adjusted to 10.0 by additionof 5 N NaOH and maintained for 4 hours. The EtOAc was removed byconcentration in vacuo, then the pH was adjusted to 1.0 by addition ofconcentrated HCl. The mixture was placed in a freezer overnight. Themixture was filtered and the solid was washed with water until thefiltrate stream was colorless. The solid was dried in vacuo at 50° C. togive 9.77 g of off-white solid. The solid was added to 50 mL of 2.5 NNaOH and the thick orange mixture was stirred for 3 hours. The pH wasadjusted to 1.0 with concentrated HCl. The mixture was filtered and thesolid was washed with water. The solid was dried to 9.43 g of off-whitesolid. The solid was dissolved in 200 mL of boiling MeOH and the hotsolution was filtered, then cooled to room temperature. Water (300 mL)was added, and the mixture was stirred at room temperature for 2 hours.The solid was filtered off and washed with 100 mL of a 1:1 mixture ofMeOH and water. The solid was dried in vacuo at 50° C. to give 7.18 g ofthe intermediate title compound as a white solid (HPLC: 97%, 83% yield).

Preparation of 5-Methoxy-2-naphthylamine.

5-Methoxy-2-naphthoic acid (3.17 g, 15.7 mmol), CH₂Cl₂ (38 mL) and DMF(3.04 mL, 39.2 mmol) were combined in a 50-mL flask under a N₂atmosphere. Oxalyl chloride (2.73 mL, 31.3 mmol) was added dropwise over30 minutes at 20 to 23° C. The resulting yellow solution was stirred atroom temperature for 15 minutes. The solution was then concentrated invacuo to give 6.48 g of yellow solid which was slightly wet with DMF.The solid was dissolved in CH₃CN (157 mL) and added dropwise over 35minutes to a solution of sodium azide (2.55 g, 39.2 mmol) in 24 mL ofwater, and rinsed in with an additional 25 mL of CH₃CN. Analysis of theresulting yellow mixture by HPLC after 5 minutes showed 15% acylchloride remaining. Water (15 mL) was added to give an orange mixtureand to promote acyl azide formation. The mixture was heated at refluxfor 1 hour and 40 minutes. The mixture was cooled to room temperature.Sodium hydroxide (50 mL, 2 N solution) was added and the resultingyellow mixture was stirred at room temperature overnight. The mixturewas concentrated in vacuo to yield 102.0 g of brown gum plus liquid. Themixture was extracted with 50 mL of CH₂Cl₂. The CH₂Cl₂ layer was driedover Na₂SO₄, filtered and concentrated in vacuo to provide 1.83 g of theintermediate title compound as a brown oil (HPLC: 91%, 61% yield).

Preparation of Final Title Compound.

2-Amino-5-methoxynaphthalene (1.78 g, 9.35 mmol), 5 mL of concentratedHCl_((aq)), 5 mL of water and 10 g of ice were combined in a flask. Thetan orange mixture was cooled to 5° C. A chilled solution of sodiumnitrite (0.75 g, 10.8 mmol) in 4 mL of water was added over 5 minutes,keeping the temperature below 10° C. The mixture was stirred at 5° C.for 30 minutes. A solution of potassium iodide (1.71 g, 10.3 mmol) in10.5 mL of water was added, the bath was removed and the orange solutionplus black solid was stirred at room temperature. Analysis by HPLCshowed that more KI was needed. Potassium iodide (7.2 g, 43.4 mmol), 100mL of CH₃CN and 50 mL of acetone were added, and the mixture was stirredfor 22 hours at room temperature. The mixture was extracted with 150 mLof Et₂O. The Et₂O phase was washed successively with 200 mL of 5%NaHSO_(3(aq)), 200 mL of 5% NaHCO_(3(aq)), 200 mL of water and 200 mL ofsaturated NaCl solution. The Et₂O phase was dried over Na₂SO₄, filteredand concentrated in vacuo to 2.21 g of dark brown solid (HPLC: 69.5%).The solid was adsorbed onto 8.0 g of silica gel 60 in CH₂Cl₂ thenconcentrated to a powder. The powder was slurried in hexanes andchromatographed on 100 g of silica gel 60 at atmospheric pressure,eluting with hexanes. The desired final title compound was collected(1.33 g, 50% yield) as a white solid after concentration of theappropriate fractions.

Preparation 4 Preparation of N-t-Butyloxycarbonyl-2-methyl-4-piperidone

A solution of the following protected amine;

(145 g, prepared in a manner analogous to the procedures described byHall, H. K. Jr., J. Am. Chem. Soc., 79, 5444 (1957) and Harper, N. J.;Beckett, A. H.; Balon, A. D. J., J. Chem. Soc., 2704 (1960)) dissolvedin THF (200 mL) was added dropwise over one hour to a cooled solution ofpotassium t-butoxide (58.9 g) in THF (500 mL). The mixture was stirredat 0° C. for 2.5 hours and then warmed to room temperature over 1 hourswhile stirring. Another 50 mL of 1.0 M potassium t-butoxide in THF wasadded. After one hour, the solvent was removed under vacuum and theresidue was dissolved in ethyl acetate (1 L). The organic solution waswashed with saturated ammonium chloride (2×500 mL) which was backextracted with ethyl acetate (2×500 mL). The organic extracts werecombined, dried over anhydrous magnesium sulfate, filtered andconcentrated under vacuum to provide 120.6 g of the crude material as anoil. This oil was then treated with 5 N HCl (700 mL) at reflux for about14.5 hours. After cooling, the solution was rinsed with a mixture ofethyl acetate/diethyl ether (1:1, 2×300 mL). The aqueous layer was thenconcentrated to provide the piperidone salt of structure:

The above piperidone salt was then dissolved in water (200 mL) and THF(250 mL). The solution was then cooled to 0° C. and treated with 50%sodium hydroxide (35 mL), followed by dropwise addition oftert-butoxycarbonyl anhydride (106.7 g) in THF (100 mL) over one hourperiod. The ice bath was then removed and the solution was stirred atroom temperature for about 4 days. The pH was adjusted to about 8 to 9.The THF was then removed under vacuum and the mixture was taken up inethyl acetate (500 mL). The layers were separated and the aqueous layerwas extracted with ethyl acetate (2×500 mL). The organic extracts werecombined, washed with brine (300 mL), dried over anhydrous magnesiumsulfate, filtered and concentrated under vacuum. The residue waspurified by chromatography on silica gel (ethyl acetate/hexanes) toprovide 36.81 g of the title compound.

Preparation 5 Preparation ofN-t-Butyloxycarbonyl-2,2-dimethyl-4-piperidone

In a manner analogous to the procedure described in preparation 4 above,the title compound was prepared from the following starting material;

Preparation 6 Preparation of N-Benzyl-3,3-dimethyl-4-piperidone

In a 1 liter 3-neck flask equipped with a mechanical stirrer, anaddition funnel and a calcium chloride drying tube was added a 37%weight solution of formaldehyde (168.5 mL, 2.25 mole) dissolved in 500mL of absolute ethanol. The resulting solution was cooled in anice-water bath to 10° C., and benzylamine (109 mL, 1 mole) was addeddropwise over a one hour period. In a separate 3-liter 3-neck flaskequipped with a mechanical stirrer, an addition funnel and twocondensers was added 3-methyl-2-butanone (113 mL, 1.06 mole) dissolvedin 500 ml of absolute ethanol and concentrated hydrogen chloride (92 mL,1.11 mole). The resulting solution was brought to reflux and theformaldehyde/benzylamine solution is added dropwise over a 2 hourperiod. This solution was heated at reflux overnight, and then cooled toambient temperature. Diisopropylethylamine (142.2 g, 1.1 mole) andformaldehyde (22.46 mL, 0.3 mole) were added and the resulting solutionwas heated to reflux for six hours, and then cooled to ambienttemperature. The solution was quenched with potassium hydroxide (61.6 g,1.1 mole) in 200 mL of water, and then extracted 3 times with 500 mlethyl acetate. The organic layers were concentrated under vacuum to give225 g of a red oil. The crude oil was dissolved in 1 liter of methylenechloride. This solution was carefully poured over 1 kg of silica gel ona sintered glass filter. The silica gel was washed with 4 L of methylenechloride. The methylene chloride was concentrated under vacuum toprovide 142 g of a yellow oil which was crystallized in a freezerovernight. Yield=65.4%. MS(ion spray)=218.3(M+1)

Preparation 7 Preparation of:

To 24.1 g (0.12 mol) of 4-bromothiophenol was added 168 mL of H₂O and5.6 g (0.13 mol) of NaOH beads. To the resulting slurry was added 11.8 g(0.12 mol) of chloroacetone over 10 min. After 2.5 h, the product wasremoved by filtration and rinsed with H₂O. After drying under vacuum at35° C. for 3 days, 29.5 g (99%) of title compound was obtained as anoff-white solid.

Preparation 8 Preparation of 5-bromo-3-methylbenzo[b]thiophene

Amberlyst-15 resin (10 g) was slurried in 75 mL of chlorobenzene and themixture was heated to reflux. Solvent was distilled and fresh solventwas added at an equal rate until 100 mL of solvent had been collected. Asolution of 10.0 g (0.041 mol) of the ketone prepared in preparation 7above in 50 mL of chlorobenzene was added dropwise over 3 h. Solvent wasremoved by distillation during the addition and 80 mL of additionalchlorobenzene was added to maintain a constant volume. The mixture wasallowed to cool room temperature and filtered. The resin was rinsed with50 mL of chlorobenzene and the filtrate was evaporated to 9.38 g (100%)of title compound.

EXAMPLE 1 Preparation of(2S)-(−)-3-[(2R,4R)-4-(6-Methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-2-propanoloxalate

Preparation of (2S)-4-Glycidyloxy-2-methylindole.

Scheme IV, Step A: To a solution of 4-hydroxy-2-methylindole (19.91 g,135 mmol), dissolved in DMF (200 mL) at 0° C., was added sodium hydride(80% dispersion in mineral oil, 4.26 g, 142.0 mmol). The greensuspension was stirred for 1 h. A solution of (S)-glycidyl nosylate(35.06 g, 135.2 mmol) in 70 mL of DMF was then added dropwise via acannula and stirred for 10 min. The reaction mixture was stored in thefreezer for 15 h, stirred at 0° C. for 4 h, and quenched with 500 mL ofH₂O. The resulting solution was then extracted with (3×300 mL) EtOAc.The organic layers were washed with (5×300 mL) H₂O, dried over MgSO₄,filtered and concentrated. The crude product was crystallized fromCH₂Cl₂ and rinsed with pentane. The mother liquor was concentrated andpurified by silica gel chromatography (25% hexanes/CH₂Cl₂). Thematerials were combined to give the intermediate title compound asyellow crystals (21.24 g, 77%). IR (KBr) 3473, 1096 cm⁻¹. Ion Spray MS204.2 (M+H)⁺, 202.3 (M−H)⁻. C₁₂H₁₃NO₂

analysis: calculated found C 70.92 71.16 H  6.45  6.51 N  6.89  6.93Preparation of(±)N-t-Butoxycarbonyl-4-hydroxy-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Step A: To a solution of 6-methoxybenzo[b]thiophene (5.0 g,30.4 mmol) in dry THF (60 mL) at −78° C. was added 1.6 M n-BuLi inhexanes (20.9 mL, 33.44 mmol). The solution was stirred at −78° C. for90 min. The N-t-butoxycarbonyl-2-methyl-4-piperidone (3.89 g, 18.24mmol) dissolved in THF (40 mL) was added via a cannula at −78° C. Thereaction mixture was stirred at −78° C. for 3 h. The reaction was thenquenched with 75 mL of saturated aqueous NaCl solution. The mixture wasextracted with (1×75 mL, 2×125 mL) EtOAc. The combined organic layerswere dried over CaCl₂ and filtered. The filtrate was concentrated andpurified by medium pressure chromatography (30% Et₂O/hexanes) to givethe intermediate title compound as a yellow foam (1.798 g, 26%). IR(KBr) 3009, 2978 cm⁻. Ion Spray MS 378 (M+H)⁺; 436 (M+CH₃COO⁻)⁻.

Preparation of(±)-cis-4-(6-Methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-hydroxy-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine(1.734 g, 4.59 mmol) in dry CH₂Cl₂ (13 mL) at 0° C. was added 5.8 mL oftrifluoroacetic acid. The resulting purple solution was stirred at 0° C.for 16 h. The reaction was then quenched at 0° C. with saturated aqueousNaHCO₃ solution (75 mL). The mixture was extracted with (2×150 mL)CH₂Cl₂. The combined organic layers were dried over CaCl₂, filtered, andconcentrated. The residue was partitioned between saturated aqueousNaHCO₃ and CH₂Cl₂ and the layers were separated. The organic layer wasdried over MgSO₄ and concentrated to yield 0.9 g of crude regioisomericolefins. To a solution of the crude olefins (0.90 g) in a mixture ofethanol (29.7 mL) and 2,2,2-trifluoroethanol (10 mL) was added 10% Pd/C(1.00 g). The black slurry was stirred vigorously at room temperatureunder hydrogen (balloon pressure) for one day. The black slurry was thenfiltered through a pad of Celite and washed with ethanol. The filtratewas concentrated and the residue was purified by flash chromatography[4.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the intermediate titlecompound as green powder (0.321 g, 35%). IR (KBr) 2936, 1478, 839 cm⁻¹.Ion Spray 262.1 (M+H)⁺. C₁₅H₁₉NOS

analysis: calculated found C 68.93 69.18 H  7.33  7.05 N  5.36  5.17Preparation of(±)-trans-4-(6-Methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-hydroxy-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine(1.734 g, 4.59 mmol) in dry CH₂Cl₂ (13 mL) at 0° C. was added 5.8 mL oftrifluoroacetic acid. The resulting purple solution was stirred at 0° C.for 16 h. The reaction was quenched at 0° C. with saturated aqueousNaHCO₃ solution (75 mL). The mixture was extracted (2×150 mL) withCH₂Cl₂. The combined organic layers were dried over CaCl₂, filtered, andthe filtrate was concentrated. The residue was partitioned betweensaturated aqueous NaHCO₃ and CH₂Cl₂. The layers were separated, and theorganic layer was dried over MgSO₄ and concentrated to give 0.9 g ofcrude regioisomeric olefins. To a solution of the crude olefins (0.90 g)in a mixture of ethanol (29.7 mL) and 2,2,2-trifluoroethanol (10 mL) wasadded 10% Pd/C (1.00 g). The black slurry was stirred vigorously at roomtemperature under hydrogen (balloon pressure) for one day. The blackslurry was filtered through a pad of Celite and washed with ethanol. Thefiltrate was then concentrated and the residue was purified by flashchromatography [4.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to provide theintermediate title compound as a yellow/green oil (0.2295 g, 25%). IR(KBr) 2936, 1478, 840 cm⁻¹. Ion Spray 262.1 (M+H)⁺.

Preparation of the Final Title Compound.

Scheme IV, Step B: A solution of(±)-cis-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.118 g,0.451 mmol) and (2S)-4-glycidyloxy-2-methylindole (0.092 g, 0.451 mmol)in MeOH (6 mL) was heated at reflux for 15 h and then cooled andevaporated. The residue was purified by silica gel chromatography [3%(2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base of the final titlecompound as a yellow oil (0.0708 g, 34%). The oxalate salt was preparedwith 1 eq. of oxalic acid in EtOAc. mp 108° C. (dec.). IR (KBr) 3473,1058 cm⁻¹. Ion Spray MS 465 (M+H)⁺; 463 (M−H)⁻. [α]_(D) =−40 (c 0.60,CHCl₃). C₂₇H₃₂N₂O₃S.0.4CH₂Cl₂

analysis: calculated found C 65.99 66.12 H  6.64  6.86 N  5.61  5.52

EXAMPLE 2 Preparation of(2S)-(−)-3-[(2S,4S)-4-(6-Methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.118 g,0.451 mmol, prepared in example 1) and (2S)-4-glycidyloxy-2-methylindole(0.092 g, 0.451 mmol, prepared in example 1) in MeOH (6 mL) was heatedat reflux for 15 h and then cooled and evaporated. The residue waspurified by silica gel chromatography [3% (2.0 M NH₃ in MeOH)/CH₂Cl₂] togive the free base of the title compound as a yellow oil (0.0664 g,32%). The oxalate salt was prepared with 1 eq. of oxalic acid in EtOAc.mp 117.9° C. (dec.). IR (KBr) 3473, 1058 cm⁻¹. Ion Spray MS 465 (M+H)⁺;463 (M−H)⁻. [α]_(D)=−7.52 (c 0.532, CHCl₃). C₂₇H₃₂N₂O₃S.C₂H₂O₄.0.2C₄H₈O₂

analysis: calculated found C 62.50 62.23 H  6.28  6.25 N  4.89  4.70

EXAMPLE 3 Preparation of(2S)-(−)-3-[(2S,4R)-4-(6-Methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.103g, 0.394 mmol, prepared in example 1) and(2S)-4-glycidyloxy-2-methylindole (0.801 g, 0.394 mmol, prepared inexample 1) in MeOH (6 mL) was heated at reflux for 18 h and then cooledand evaporated. The residue was purified by silica gel chromatography[5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base of the titlecompound as a white foam (0.0608 g, 33%). The oxalate salt was preparedas in example 1. mp 109.8° C. (dec.). IR (KBr) 3473, 1058 cm⁻¹. IonSpray MS 465 (M+H)⁺; 463 (M−H)⁻. [α]_(D)=−28.17 (c 0.497, CHCl₃).C₂₇H₃₂N₂O₃S.C₂H₂O₄

analysis: calculated found C 62.80 62.95 H  6.18  6.19 N  5.05  4.76

EXAMPLE 4 Preparation of(2S)-(−)-3-[(2R,4S)-4-(6-Methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.103g, 0.394 mmol, prepared in example 1) and(2S)-4-glycidyloxy-2-methylindole (0.801 g, 0.394 mmol, prepared inexample 1) in MeOH (6 mL) was heated at reflux for 18 h and then cooledand evaporated. The residue was purified by silica gel chromatography[5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base of the titlecompound as an amorphous white solid (0.084 g, 46%). The oxalate saltwas prepared as in example 1. mp 117.5° C. (dec.). IR (KBr) 3473, 1058cm⁻¹. Ion Spray MS 465 (M+2H)⁺; 463 (M−H)⁻. [α]_(D)=−11.59 (c 0.345,CHCl₃). C₂₇H₃₂N₂O₃S.C₂H₂O₄

analysis: calculated found C 62.80 61.14 H  6.18  5.97 N  5.05  5.04

EXAMPLE 5 Preparation of (2S)-(−)-3-[(2R,4R)-4-(4-Methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.607 g,2.32 mmol, prepared in a manner analogous to the preparation of(±)-cis-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine inexample 1) and (2S)-4-glycidyloxy-2-methylindole (0.472 g, 2.32 mmol,prepared in example 1) in MeOH (30 mL) was heated at reflux for 15 h andthen cooled and evaporated. The residue was purified by silica gelchromatography [1% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a green foam (0.4758 g, 44%). The oxalate salt wasprepared as in example 1. mp 124.5° C. (dec.). IR (KBr) 3473, 1049 cm⁻¹.Ion Spray MS 465 (M+H)⁺; 463 (M−H)⁻. [α]_(D)=−29.25 (c 0.547, CHCl₃).C₂₇H₃₂N₂O₃S.C₂H₂O₄

analysis: calculated found C 62.80 62.53 H  6.18  6.38 N  5.05  4.97

EXAMPLE 6 Preparation of(2S)-3-[(2S,4S)-4-(4-Methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.607 g,2.32 mmol, prepared in a manner analogous to the preparation of(±)-cis-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine inexample 1) and (2S)-4-glycidyloxy-2-methylindole (0.472 g, 2.32 mmol,prepared in example 1) in MeOH (30 mL) was heated at reflux for 15 h andthen cooled and evaporated. The residue was purified by silica gelchromatography [1% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a green powder (0.431 g, 40%). The oxalate saltwas prepared as in example 1. mp 117.8° C. (dec.). IR (KBr) 3473, 1049cm⁻¹. Ion Spray MS 465 (M+H)⁺; 463 (M−H)⁻. [α]_(D)=0.00 (c 0.593,CHCl₃). C₂₇H₃₂N₂O₃S.C₂H₂O₄

analysis: calculated found C 62.80 62.55 H  6.18  6.27 N  5.05  5.13

EXAMPLE 7 Preparation of(2S)-(−)-3-[(2S,4R)-4-(4-Methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.123g, 0.470 mmol, prepared in a manner analogous to the preparation of(±)-trans-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine inexample 1) and (2S)-4-glycidyloxy-2-methylindole (0.96 g, 0.47 mmol,prepared in example 1) in MeOH (7 mL) was heated at reflux for 15 h andthen cooled and evaporated. The residue was purified by silica gelchromatography [3% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a yellow foam (0.101 g, 46%). The oxalate salt wasprepared with 1 eq. of oxalic acid in EtOAc. mp 114.9° C. (dec.). IR(KBr) 3473, 1050 cm⁻¹. Ion Spray MS 465 (M+H)⁺; 463 (M−H)⁻.[α]_(D)=−23.39 (c 0.513, CHCl₃). C₂₇H₃₂N₂O₃S

analysis: calculated found C 69.8  69.97 H  6.94  7.05 N  6.03  6.00Preparation of(2S)-(−)-3-[(2S,4R)-4-(4-Methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanolhydrochloride.

A solution of(±)-trans-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.852g, 3.262 mmol) and (2S)-4-glycidyloxy-2-methylindole (0.96 g, 3.262mmol) in methanol (45 mL) was heated at reflux for 20 h and then cooledand evaporated. The residue was purified by silica gel chromatography [1to 6% (2.0 M NH₃ in MeOH)/CH₂Cl₂, to give the free amine as a yellowfoam (0.743 g, 49%). The hydrochloride salt was prepared with 1 eq. of1.0 M HCl in diethyl ether using EtOAc (10 mL) as the solvent. Ion SprayMS 465 (M+H)⁺; 523 (M+CH₃COO⁻)⁻. C₂₇H₃₂N₂O₃S.0.6H₂O

analysis: calculated found C 63.35 63.13 H  6.73  6.60 N  5.47  5.50

EXAMPLE 8 Preparation of(2S)-(−)-3-[(2R,4S)-4-(4-Methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.123g, 0.470 mmol, prepared in a manner analogous to the preparation of(±)-trans-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine inexample 1) and (2S)-4-glycidyloxy-2-methylindole (0.96 g, 0.47 mmol,prepared in example 1) in MeOH (7 mL) was heated at reflux for 15 h andthen cooled and evaporated. The residue was purified by silica gelchromatography [3% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a green oil (0.106 g, 49%). The oxalate salt wasprepared with 1 eq. of oxalic acid in EtOAc. mp 123.5° C. (dec.). IR(KBr) 3473, 1050 cm⁻¹. Ion Spray MS 465 (M+H)⁺; 463 (M−H)⁻.[α]_(D)=−13.64 (c 0.44, CHCl₃). C₂₇H₃₂N₂O₃S.C₂H₂O₄

analysis: calculated found C 62.80 62.63 H  6.18  6.37 N  5.05  5.00

EXAMPLE 9 Preparation of4-[(2S)-(−)-2-Hydroxy-3-[(2R,4R)-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]propoxy]indole-2-carboxamideoxalate

Scheme IV, Step B: A solution of(±)-cis-4-(6-methoxybenzo[b]thiophenyl)-2-methylpiperidine (0.123 g,0.470 mmol, prepared in example 1) and(2S)-4-glycidyloxy-2-indolecarboxamide (0.270 g, 1.16 mmol, prepared ina manner analogous to the preparation of(2S)-4-glycidyloxy-2-methylindole in example 1) in MeOH (15 mL) washeated at reflux for 8 h and then cooled and allowed to stir for 4 days.The solution was then heated at reflux overnight, cooled, and thesolvent was evaporated. The residue was purified by silica gelchromatography [2% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a yellow solid (0.308 g, 57%). The oxalate saltwas prepared with 1 eq. of oxalic acid in EtOAc. mp 109.5° C. (dec.). IR(KBr) 1668 cm⁻¹. Ion Spray MS 494 (M+H)⁺; 492 (M−H)⁻. [α]_(D)=−20.91 (c0.574, CHCl₃). C₂₇H₃₁N₃O₄S.C₂H₂O₄

analysis: calculated found C 59.68 59.80 H  5.70  5.96 N  7.20  6.96

EXAMPLE 10 Preparation of4-[(2S)-(−)-2-Hydroxy-3-[(2S,4S)-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]propoxy]indole-2-carboxamideoxalate

Scheme IV, Step B: A solution of(±)-cis-4-(6-methoxybenzo[b]thiophenyl)-2-methylpiperidine (0.123 g,0.470 mmol, prepared in example 1) and(2S)-4-glycidyloxy-2-indolecarboxamide (0.270 g, 1.16 mmol, prepared ina manner analogous to the preparation of(2S)-4-glycidyloxy-2-methylindole in example 1) in MeOH (15 mL) washeated at reflux for 8 h and then cooled and allowed to stir for 4 days.The solution was then heated at reflux overnight, cooled, and thesolvent was evaporated. The residue was purified by silica gelchromatography [2% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a white solid (0.2069 g, 38.2%). The oxalate saltwas prepared with 1 eq. of oxalic acid in EtOAc. mp 130.8° C. (dec.). IR(KBr) 1668 cm⁻¹. Ion Spray MS 494 (M+H)⁺; 492 (M−H)⁻. [α]_(D)=−3.91 (C0.512, CHCl₃). C₂₇H₃₁ N₃O₄S.0.1CH₂Cl₂.0.3H₂O

analysis: calculated found C 64.12 63.84 H  6.32  6.40 N  8.27  8.09

EXAMPLE 11 Preparation of4-[(2S)-(−)-2-Hydroxy-3-[(2S,4R)-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]propoxy]indole-2-carboxamideoxalate

Scheme IV, Step B: A solution of(±)-trans-4-(6-methoxybenzo[b]thiophenyl)-2-methyl piperidine (0.221 g,0.845 mmol, prepared in example 1) and(2S)-4-glycidyloxy-2-indolecarboxamide (0.196 g, 0.845 mmol, prepared ina manner analogous to the preparation of(2S)-4-glycidyloxy-2-methylindole in example 1) in MeOH (12.0 mL) washeated at reflux for 8 h and then cooled and allowed to stir for 4 days.The solution was then heated at reflux overnight, cooled, and thesolvent was evaporated. The residue was purified by silica gelchromatography [2% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a yellow solid (0.1684 g, 40%). The oxalate saltwas prepared with 1 eq. of oxalic acid in EtOAc. mp 116.8° C. (dec.). IR(KBr) 3454, 1668 cm⁻¹. Ion Spray MS 494 (M+H)⁺; 492 (M−H)⁻.[α]_(D)=−16.98 (c 0.589, CHCl₃). C₂₇H₃₁N₃O₄S.0.1C₄H₈O₂.0.6H₂O.C₂H₂O₄

analysis: calculated found C 58.53 58.28 H  5.86  5.81 N  6.96  7.01

EXAMPLE 12 Preparation of4-[(2S)-(−)-2-Hydroxy-3-[(2R,4S-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]propoxy]indole-2-carboxamideoxalate

Scheme IV, Step B: A solution of(±)-trans-4-(6-methoxybenzo[b]thiophenyl)-2-methyl piperidine (0.221 g,0.845 mmol, prepared in example 1) and(2S)-4-glycidyloxy-2-indolecarboxamide (0.196 g, 0.845 mmol, prepared ina manner analogous to the preparation of(2S)-4-glycidyloxy-2-methylindole in example 1) in MEOH (12.0 mL) washeated at reflux for 8 h and then cooled and allowed to stir for 4 days.The solution was then heated at reflux overnight, cooled, and thesolvent was evaporated. The residue was purified by silica gelchromatography [2% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a yellow solid (0.1461 g, 35%). The oxalate saltwas prepared with 1 eq. of oxalic acid in EtOAc. mp 113.2° C. (dec.). IR(KBr) 1668 cm⁻¹. Ion Spray MS 494 (M+H)⁺; 492 (M−H)⁻. [α]_(D)=−19.8 (c0.505, CHCl₃). C₂₇H₃₁ N₃O₄S.C₂H₂O₄.0.1C₄H₈O₂.0.6H₂O

analysis: calculated found C 58.53 58.18 H  5.85  5.74 N  6.97  6.94

EXAMPLE 13 Preparation of(2S)-(−)-1-(1H-2-Methylindol-4-yl)oxy-3-[(2R,4R)-2-methyl-4-(4-methylbenzo[b]thiophen-2-yl)piperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(4-methylbenzo[b]thiophen-2-yl)-2-methylpiperidine (0.191 g,0.778. mmol, prepared in a manner analogous to the preparation of(±)-cis-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine inexample 1) and (2S)-4-glycidyloxy-2-methylindole (0.158 g, 0.778 mmol,prepared in example 1) in MeOH (10 mL) was heated at reflux for 15 h andthen cooled and evaporated. The residue was purified by silica gelchromatography [1.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free baseof the title compound as a yellow foam (0.1332 g, 38%). The oxalate saltwas prepared with 1 eq. of oxalic acid in EtOAc. mp 106.5° C. (dec.). IR(KBr) 3473 cm⁻¹. Ion Spray MS 449 (M+H)⁺; 447 (M−H)⁻. [α]_(D)=−32.79 (c0.4269, CHCl₃). C₂₇H₃₂N₂O₂S.C₂H₂O₄

analysis: calculated found C 64.66 64.49 H  6.36  6.60 N  5.20  5.35

EXAMPLE 14 Preparation of(2S)-(−)-1-(1H-2-Methylindol-4-yl)oxy-3-[(2S,4S)-2-methyl-4-(4-methylbenzo[b]thiophen-2-yl)piperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(4-methylbenzo[b]thiophen-2-yl)-2-methylpiperidine (0.191 g,0.778 mmol, prepared in a manner analogous to the preparation of(±)-cis-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine inexample 1) and (2S)-4-glycidyloxy-2-methylindole (0.158 g, 0.778 mmol,prepared in example 1) in MeOH (10 mL) was heated at reflux for 15 h andthen cooled and evaporated. The residue was purified by silica gelchromatography [1.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free baseof the title compound as a white foam (0.1405 g, 40%). The oxalate saltwas prepared with 1 eq. of oxalic acid in EtOAc. mp 84.3° C. (dec.). IR(KBr) 3473 cm⁻¹. Ion Spray MS 449 (M+H)⁺; 447 (M−H)⁻. [α]_(D)=−4.48 (c0.4464, CHCl₃). C₂₇H₃₂N₂O₂S

analysis: calculated found C 72.29 72.58 H  7.19  7.20 N  6.24  6.43

EXAMPLE 15 Preparation of(2S)-(−)-1-(1H-2-Methylindol-4-yl)oxy-3-[(2S,4R)-2-methyl-4-(4-methylbenzo[b]thiophen-2-yl)piperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(4-methylbenzo[b]-thiophenyl)-2-methylpiperidine (0.100 g,0.407 mmol, prepared in a manner analogous to the preparation of(±)-trans-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine inexample 1) and (2S)-4-glycidyloxy-2-methylindole (0.083 g, 0.407 mmol,prepared in example 1) in MeOH (6 mL) was heated at reflux for 15 h andthen cooled and evaporated. The residue was purified by silica gelchromatography [1.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free baseof the title compound as a yellow solid (0.0768 g, 42%). The oxalatesalt was prepared with 1 eq. of oxalic acid in EtOAc. mp 121.3° C.(dec.). IR (KBr) 3473 cm⁻¹. Ion Spray MS 449 (M+H)⁺; 447 (M−H)⁻.[α]_(D)=−25.42 (c 0.5507, CHCl₃). C₂₇H₃₂N₂O₂S

analysis: calculated found C 72.29 72.07 H  7.19  7.32 N  6.24  6.45

EXAMPLE 16 Preparation of(2S)-(−)-1-(1H-2-methylindol-4-yl)oxy-3-[(2R,4S)-2-Methyl-4-(4-methylbenzo[b]thiophen-2-yl)piperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(4-methylbenzo[b]thiophenyl)-2-methylpiperidine (0.100 g,0.407 mmol, prepared in a manner analogous to the preparation of(±)-trans-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine inexample 1) and (2S)-4-glycidyloxy-2-methylindole (0.083 g, 0.407 mmol,prepared in example 1) in MeOH (6 mL) was heated at reflux for 15 h andthen cooled and evaporated. The residue was purified by silica gelchromatography [1.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free baseof the title compound as a green solid (0.0818 g, 45%). The oxalate saltwas prepared with 1 eq. of oxalic acid in EtOAc. mp 109.1° C. (dec.). IR(KBr) 3473 cm⁻¹. Ion Spray MS 449 (M+H)⁺; 447 (M−H)⁻. [α]_(D)=−18.61 (c0.5374, CHCl₃). C₂₇H₃₂N₂O₂S.C₂H₂O₄.1.0H₂O.0.2C₄H₈O₂

analysis: calculated found C 62.32 61.96 H  6.60  6.57 N  4.88  5.14

EXAMPLE 17 Preparation of(2S)-(−)-3-[(2R,4R)-4-(5-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(5-chlorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.1885 g,0.709 mmol, prepared in a manner analogous to the preparation of(±)-cis-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine inexample 1) and (2S)-4-glycidyloxy-2-methylindole (0.144 g, 0.709 mmol,prepared in example 1) in MeOH (10 mL) was heated at reflux for 15 h andthen cooled and evaporated. The residue was purified by silica gelchromatography [4% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a yellow solid (0.1473 g, 44%) The oxalate saltwas prepared with 1 eq. of oxalic acid in EtOAc. mp 82.1° C. (dec.). IR(KBr) 3473 cm⁻¹. Ion Spray MS 469 (M+H)⁺; 467 (M−H)⁻. [α]_(D)=−28.07 (c0.4988, CHCl₃). C₂₆H₂₉CIN₂O₂S.C₂H₂O₄

analysis: calculated found C 60.15 59.85 H  5.59  5.57 N  5.01  4.77

EXAMPLE 18 Preparation of(2S)-(−)-3-[(2S,4S)-4-(5-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate.

Scheme IV, Step B: A solution of(±)-cis-4-(5-chlorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.1885 g,0.709 mmol, prepared in a manner analogous to the preparation of(±)-cis-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine inexample 1) and (2S)-4-glycidyloxy-2-methylindole (0.144 g, 0.709 mmol,prepared in example 1) in MeOH (10 mL) was heated at reflux for 15 h andthen cooled and evaporated. The residue was purified by silica gelchromatography [4% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a transparent oil (0.0429 g, 13%). The oxalatesalt was prepared with 1 eq. of oxalic acid in EtOAc. mp 105.0° C.(dec.). IR (KBr) 3473 cm⁻¹. Ion Spray MS 469 (M+H)⁺; 467 (M−H)⁻.[α]_(D)=−11.59 (C0.345, CHCl₃). C₂₆H₂₉ClN₂O₂S.C₂H₂O₄

analysis: calculated found C 60.15 60.32 H  5.59  5.78 N  5.01  5.04

EXAMPLE 19 Preparation of(2S)-(−)-3-[(2S,4R)-4-(5-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate.

Scheme IV, Step B: A solution of(±)-trans-4-(5-chlorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.1443g, 0.542 mmol, prepared in a manner analogous to the preparation of(±)-trans-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine inexample 1) and (2S)-4-glycidyloxy-2-methylindole (0.110 g, 0.542 mmol,prepared in example 1) in MeOH (8 mL) was heated at reflux for 15 h andthen cooled and evaporated. The residue was purified by silica gelchromatography [4% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a white foam (0.109 g, 43%). The oxalate salt wasprepared with 1 eq. of oxalic acid in EtOAc. mp 88.5° C. (dec.). IR(KBr) 3473 cm⁻¹. Ion Spray MS 469 (M+H)⁺; 467 (M−H)⁻. [α]_(D)=−21.33 (c0.4689, CHCl₃). C₂₆H₂₉ClN₂O₂S.C₂H₂O₄

analysis: calculated found C 60.15 60.02 H  5.59  5.87 N  5.01  4.80

EXAMPLE 20 Preparation of(2S)-(−)-3-[(2R,4S)-4-(5-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(5-chlorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.1443g, 0.542 mmol, prepared in a manner analogous to the preparation of(±)-trans-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine inexample 1) and (2S)-4-glycidyloxy-2-methylindole (0.110 g, 0.542 mmol,prepared in example 1) in MeOH (8 mL) was heated at reflux for 15 h andthen cooled and evaporated. The residue was purified by silica gelchromatography [4% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a white foam (0.0925 g, 36%). The oxalate salt wasprepared with 1 eq. of oxalic acid in EtOAc. mp 98.5° C. (dec.). IR(KBr) 3473 cm⁻¹. Ion Spray MS 469 (M+H)⁺; 467 (M−H)⁻. [α]_(D)=−28.06 (c0.4689, CHCl₃). C₂₆H₂₉ClN₂O₂S.C₂H₂O₄

analysis: calculated found C 60.15 60.17 H  5.59  5.83 N  5.01  5.17

EXAMPLE 21 Preparation of(2S)-(−)-3-[4-(4-Methylbenzo[b]thiophen-2-yl)piperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of4-(4-methylbenzo[b]thiophen-2-yl)piperidine (0.1609 g, 0.695 mmol,prepared in a manner analogous to the preparation of(±)-cis-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine inexample 1) and (2S)-4-glycidyloxy-2-methylindole (0.141 g, 0.695 mmol,prepared in example 1) in MeOH (10 mL) was heated at reflux for 15 h andthen cooled and evaporated. The residue was purified by silica gelchromatography [1% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a green oil (0.237 g, 79%). The oxalate salt wasprepared with 1 eq. of oxalic acid in EtOAc. mp 101.9–105.5° C. (dec.).IR (KBr) 3473, 3008, 2943, 1246 cm⁻¹. Ion Spray MS 435 (M+H)⁺; 433(M−H)⁻. [α]_(D)=−19.61 (c 0.51, CHCl₃). C₂₆H₃₀N₂O₂S.C₂H₂O₄

analysis: calculated found C 64.10 63.84 H  6.15  6.17 N  5.34  5.10

EXAMPLE 22 Preparation of(2S)-(−)-3-[4-(4-Methoxybenzo[b]thiophen-2-yl)piperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of4-(4-methoxybenzo[b]thiophen-2-yl)piperidine (0.050 g, 0.202 mmol,prepared in a manner analogous to the preparation of(±)-cis-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine inexample 1) and (2S)-4-glycidyloxy-2-methylindole (0.0410 g, 0.202 mmol,prepared in example 1) in MeOH (3 mL) was heated at reflux for 21 h,cooled and evaporated. The residue was purified by silica gelchromatography [3.0% (2.0 M NH₃ in EtOH)/CH₂Cl₂] then the lower boilingsolvents was azeotropically removed with xylenes to give the free baseof the title compound as a green oil (0.0923 g, 99.9%). The oxalate saltwas prepared with 1 eq. of oxalic acid in EtOAc. IR (KBr) 3473, 3008,2942, 1247 cm⁻¹. Ion Spray MS 451.2 (M+H)⁺; 449.2 (M−H)⁻. [α9 _(D)=−16.0(c 0.500, CHCl₃). C₂₆H₃₀N₂O₃S.C₂H₂O₄

analysis: calculated found C 62.21 61.94 H  5.97  6.07 N  5.18  5.15

EXAMPLE 23 Preparation of(2S)-3-[4-(6-Methylbenzo[b]thiophen-2-yl)piperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Preparation ofN-t-Butoxycarbonyl-4-hydroxy-4-(6-methylbenzo[b]thiophen-2-yl)piperidine.

Scheme IA, Step A: To a solution of 6-methylbenzo[b]thiophene (1.25 g,8.43 mmol) in dry THF (20 mL) at −78° C. was added 1.6 M n-BuLi inhexanes (6.32 mL, 10.1 mmol). The solution was stirred at −78° C. for 40min. 1-t-Butoxycarbonyl-4-piperidone (1.84 g, 9.27 mmol) dissolved inTHF (10 mL) was added via a cannula at −78° C. The reaction mixture wasstirred at −78° C. for 3 h. The reaction was then quenched with 50 mL ofwater. The mixture was extracted (3×75 mL) with EtOAc. The combinedorganic layers were dried over MgSO₄ and filtered. The filtrate wasconcentrated to an oil and allowed to stand 3 days in which time thematerial crystallized. The crystals were rinsed with a mixture ofEtOAc/hexanes to give the intermediate title compound as yellow crystals(2.13 g, 72.6%). IR (KBr) 1681, 1429, 1246 cm⁻¹. FD+MS 347.0 (M).

Preparation of 4-(6-Methylbenzo[b]thiophen-2-yl)piperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-hydroxy-4-(6-methylbenzo[b]thiophen-2-yl)piperidine(2.14 g, 6.15 mmol) in dry CH₂Cl₂ (17.5 mL) at 0° C. was added 7.8 mL oftrifluoroacetic acid. The resulting burgundy solution was stirred at 0°C. for 15 h. The reaction was then quenched at room temperature withsaturated aqueous NaHCO₃ solution (200 mL). The resulting precipitatewas dissolved with 200 mL H₂O and was extracted (1×600 mL, 2×300 mL)with CH₂Cl₂. The combined organic layers were dried over MgSO₄, filteredand concentrated to give 0.99 g of crude regioisomeric olefins. To themixture of olefins (0.99 g) in a mixture of ethanol (36 mL) and2,2,2-trifluoroethanol (12.0 mL) was added 10% Pd/C (4.69 g). The blackslurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for three days. The black slurry was then filteredthrough a pad of Celite. The filtrate was concentrated and the residuewas purified by flash chromatography [5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] togive the intermediate title compound as a white solid (0.1192 g, 12.1%).IR (KBr) 2941, 1473, 839 cm⁻¹. Ion Spray 232.2 (M+H)⁺.

Preparation of Final Title Compound.

Scheme IV, Step B: A solution of4-(6-methylbenzo[b]thiophen-2-yl)piperidine (0.0457 g, 0.197 mmol) and(2S)-4-glycidyloxy-2-methylindole (0.0401 g, 0.1975 mmol, prepared inexample 1) in MeOH (3 mL) was heated at reflux for 15 h and then cooledand evaporated. The residue was purified by silica gel chromatography[1% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base of the final titlecompound as a yellow foam (0.0743 g, 87%). The oxalate salt was preparedwith 1 eq. of oxalic acid in EtOAc. mp 120.9° C. (dec.). IR (KBr) 3473,3008, 2943, 1247 cm⁻¹. Ion Spray MS 435 (M+H)⁺; 433 (M−H)⁻.C₂₆H₃₀N₂O₂S.C₂H₂O₄.0.9H₂O

analysis: calculated found C 62.18 61.92 H  6.30  6.62 N  5.18  5.43

EXAMPLE 24 Preparation of(2S)-(−)-1-(1H-2-Methylindol-4-yl)oxy-3-[(2R,4R)-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidinyl]-2-propanoloxalate

Preparation ofN-t-Butoxycarbonyl-4-hydroxy-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine.

Scheme IA, Step A: To a solution of 6-methylbenzo[b]thiophene (6.11 g,41.21 mmol) in dry THF (90 mL) at −78° C. was added 1.6 M n-BuLi inhexanes (30.9 mL, 49.4 mmol). The solution was stirred at −78° C. for 40min. The N-t-butoxycarbonyl-2-methyl-4-piperdone (5.27 g, 24.7 mmol)dissolved in THF (47 mL) was added via a cannula at −78° C. The reactionmixture as stirred at −78° C. for 3 h. The reaction was then quenchedwith 200 mL of water. The mixture was extracted (3×200 mL) with EtOAc.The combined organic layers were dried over MgSO₄ and filtered. Thefiltrate was concentrated and run through a column of silica gel (17%EtOAc/hexanes) to give the intermediate title compound with someunreacted N-t-butoxycarbonyl-2-methyl-4-piperidone as an orange oil(6.75 g, 45%). IR (KBr) 1680, 1418, 1366, 1158 cm⁻¹. Ion Spray MS 420(M+CH₃COO⁻)⁻.

Preparation of(±)-cis-2-Methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-hydroxy-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine(6.68 g, 18.47 mmol) in dry CH₂Cl₂ (52.0 mL) at 0° C. was added 23.45 mLof trifluoroacetic acid. The resulting purple solution was stirred at 0°C. for 15 h. The reaction was then quenched at room temperature withsaturated aqueous NaHCO₃ solution (200 mL). The mixture was extracted(3×100 mL) with CH₂Cl₂. The combined organic layers were dried overMgSO₄, filtered and concentrated to yield 4.15 g of crude regioisomericolefins. The material was run through a column of silica gel [3% (2.0 MNH₃ in MeOH)/CH₂Cl₂] to give a crude orange amorphous solid (2.36 g). Tothe mixture of olefins (2.33 g) in a mixture of ethanol (82.0 mL) and2,2,2-trifluoroethanol (27 mL) was added 10% Pd/C (10.62 g). The blackslurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for three days. The black slurry was filtered througha pad of Celite and washed with MeOH. The filtrate was concentrated andthe residue was purified by flash chromatography [4% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the intermediate title compound as a white solid(0.2442 g, 10.3%). IR (KBr) 2928, 1473, 839 cm⁻¹ . Ion Spray 246.3(M+H)⁺.

Preparation of(±)-trans-2-Methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-hydroxy-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine(6.68 g, 18.47 mmol) in dry CH₂Cl₂ (52.0 mL) at 0° C. was added 23.45 mLof trifluoroacetic acid. The resulting purple solution was stirred at 0°C. for 15 h. The reaction was then quenched at room temperature withsaturated aqueous NaHCO₃ solution (200 mL). The mixture was extracted(3×100 mL) with CH₂Cl₂. The combined organic layers were dried overMgSO₄, filtered and concentrated to yield 4.15 g of crude regioisomericolefins. The material was run through a column of silica gel 3% (2.0 MNH₃ in MeOH)/CH₂Cl₂] to give a crude orange semi-solid (2.36 g). To themixture of olefins (2.33 g) in a mixture of ethanol (82.0 mL) and2,2,2-trifluoroethanol (27 mL) was added 10% Pd/C (10.62 g). The blackslurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for three days. The black slurry was filtered througha pad of Celite and washed with MeOH. The filtrate was then concentratedand the residue was purified by flash chromatography [4% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the intermediate title compound as an orange solid(0.2017 g, 8.5%). IR (KBr) 2925, 1473, 840 cm⁻¹. Ion Spray 246.3 (M+H)⁺.

Preparation of Final Title Compound.

Scheme IV, Step B: A solution of(±)-cis-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine (0.1034 g,0.421 mmol) and (2S)-4-glycidyloxy-2-methylindole (0.0899 g, 0.442.0mmol, prepared in example 1) in MeOH (6 mL) was heated at reflux for 15h and then cooled and evaporated. The residue was purified by silica gelchromatography [1.25% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free baseof the final title compound as off-white crystals (0.0539 g, 28%). Theoxalate salt was prepared with 1 eq. of oxalic acid in EtOAc. mp 95.4°C. (dec.). IR (KBr) 3473, 3007, 2923, 1246, 1098 cm⁻¹. Ion Spray MS 449(M+H)⁺; 447 (M−H)⁻. [α]_(D)=−25.16 (c 0.477, CHCl₃). C₂₇H₃₂N₂O₂S.C₂H₂O₄

analysis: calculated found C 64.66 64.50 H  6.36  6.31 N  5.20  5.39

EXAMPLE 25 Preparation of(2S)-(−)-1-(1H-2-Methylindol-4-yl)oxy-3-[(2S,4S)-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine (0.1034 g,0.421 mmol, prepared in example 25) and(2S)-4-glycidyloxy-2-methylindole (0.0899 g, 0.442.0 mmol, prepared inexample 1) in MeOH (6 mL) was heated at reflux for 15 h and then cooledand evaporated. The residue was purified by silica gel chromatography[1.25% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base of the titlecompound as off-white crystals (0.0468 g, 24.7%). The oxalate salt wasprepared with 1 eq. of oxalic acid in EtOAc. mp 98.0° C. (dec.). IR(KBr) 3473, 3007, 2932, 1246, 1097 cm⁻¹. Ion Spray MS 449 (M+H)⁺; 447(M−H)⁻. [α]_(D)=−6.96 (c 0.575, CHCl₃). C₂₇H₃₂N₂O₂S.C₂H₂O₄.1.0H₂O

analysis: calculated found C 62.57 62.33 H  6.52  6.34 N  5.03  5.11

EXAMPLE 26 Preparation of(2S)-(−)-1-(1H-2-Methylindol-4-yl)oxy-3-[(2S,4R)-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine (0.0743g, 0.302 mmol, prepared in example 25) and(2S)-4-glycidyloxy-2-methylindole (0.0646 g, 0.317 mmol, prepared inexample 1) in MeOH (4 mL) was heated at reflux for 15 h and then cooledand evaporated. The residue was purified by silica gel chromatography[1.75% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base of the titlecompound as an off-white solid (0.0274 g, 20%). The oxalate salt wasprepared with 1 eq. of oxalic acid in EtOAc. mp 95.6° C. (dec.). IonSpray MS 449 (M+H)⁺; 447 (M−H)⁻. [α]_(D)=−23.58 (c 0.424, CHCl₃).C₂₇H₃₂N₂O₂S.0.1H₂O

analysis: calculated found C 72.00 71.84 H  7.21  7.60 N  6.22  6.13

EXAMPLE 27 Preparation of(2S)-(−)-1-(1H-2-Methylindol-4-yl)oxy-3-[(2R,4S)-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine (0.0743g, 0.302 mmol, prepared in example 25) and(2S)-4-glycidyloxy-2-methylindole (0.0646 g, 0.317 mmol, prepared inexample 1) in MeOH (4 mL) was heated at reflux for 15 h and then cooledand evaporated. The residue was purified by silica gel chromatography[1.75% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base of the titlecompound as a green oil (0.0407 g, 30%). The oxalate salt was preparedwith 1 eq. of oxalic acid in EtOAc. mp 96.5° C. (dec.). Ion Spray MS 449(M+H)⁺; 447 (M−H)⁻. [α]_(D)=−16.35 (c 0.363, CHCl₃).C₂₇H₃₂N₂O₂S.C₂H₂O₄.0.6H₂O

analysis: calculated found C 63.39 63.07 H  6.46  6.29 N  5.10  5.39

EXAMPLE 28 Preparation of(2S)-1-(1H-Indol-4-yl)oxy-3-[(2R,4R)-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine (0.11 g,0.44 mmol, prepared in example 25) and (2S)-4-glycidyloxyindole (0.0874g, 0.462.0 mmol) in MeOH (6 mL) was heated at reflux for 8 h and thencooled and allowed to stir at room temperature for 2 days. The solutionwas then heated at reflux for 4 h and then cooled and evaporated. Theresidue was purified by silica gel chromatography [1% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the title compound as anoff-white solid (0.0397 g, 20%). The oxalate salt was prepared with 1eq. of oxalic acid in EtOAc. mp 96.8° C. (dec.). Ion Spray MS 435(M+H)⁺; 433 (M−H)⁻. C₂₆H₃₀N₂O₂S

analysis: calculated found C 71.86 71.87 H  6.96  7.05 N  6.45  6.18

EXAMPLE 29 Preparation of(2S)-1-(1H-Indol-4-yl)oxy-3-[(2S,4S)-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine (0.11 g,0.44 mmol, prepared in example 25) and (2S)-4-glycidyloxyindole (0.0874g, 0.462.0 mmol) in MeOH (6 mL) was heated at reflux for 8 h and thencooled and allowed to stir at room temperature for 2 days. The solutionwas then heated at reflux for 4 h and then cooled and evaporated. Theresidue was purified by silica gel chromatography [1% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the title compound as anoff-white solid (0.0174 g, 9%). The oxalate salt was prepared with 1 eq.of oxalic acid in EtOAc. mp 89.5° C. (dec.). Ion Spray MS 435 (M+H)⁺;433 (M−H)⁻. C₂₆H₃₀N₂O₂S.C₂H₂O₄.O.4H₂O.0.1C₄H₈O₂

analysis: calculated found C 63.09 63.15 H  6.26  6.63 N  5.18  4.79

EXAMPLE 30 Preparation of(2S)-1-(1H-Indol-4-yl)oxy-3-[(2S,4R)-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine (0.070 g,0.28 mmol, prepared in example 25) and (2S)-4-glycidyloxyindole (0.056g, 0.300 mmol) in MeOH (4 mL) was heated at reflux for 8 h and thencooled and allowed to stir at room temperature for 2 days. The solutionwas then heated at reflux for 4 h and then cooled and evaporated. Theresidue was purified by silica gel chromatography [1% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the title compound as a whitesolid (0.0122 g, 10%). The oxalate salt was prepared with 1 eq. ofoxalic acid in EtOAc. mp 91° C. (dec.). Ion Spray MS 435 (M+H)⁺; 433(M−H)⁻. C₂₆H₃₀N₂O₂S.C₂H₂O₄.1.0H₂O

analysis: calculated found C 61.97 61.73 H  6.32  6.23 N  5.16  4.77

EXAMPLE 31 Preparation of(2S)-1-(1H-Indol-4-yl)oxy-3-[(2R,4S)-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine (0.070 g,0.28 mmol, prepared in example 25) and (2S)-4-glycidyloxyindole (0.056g, 0.300 mmol) in MeOH (4 mL) was heated at reflux for 8 h and thencooled and allowed to stir at room temperature for 2 days. The solutionwas then heated at reflux for 4 h and then cooled and evaporated. Theresidue was purified by silica gel chromatography [1% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the title compound as a whitesolid (0.0103 g, 10%). The oxalate salt was prepared with 1 eq. ofoxalic acid in EtOAc. mp 94.5° C. (dec.). Ion Spray MS 435 (M+H)⁺; 433(M−H)⁻. C₂₆H₃₀N₂O₂S.C₂H₂O₄.0.2H₂O

analysis: calculated found C 63.66 63.46 H  6.18  6.27 N  5.30  4.91

EXAMPLE 32 Preparation of(2S)-(+)-3-[4-(5-Chlorobenzo[b]thiophen-2-yl)piperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of the4-(5-chlorobenzo[b]thiophen-2-yl)piperidine (192.5 mg, 0.76 mmol) and(2S)-4-glycidyloxy-2-methylindole (155.4 mg, 0.76 mmol, prepared inexample 1) in MeOH (7 mL) was heated at reflux for 5.5 h. The reactionmixture was concentrated and flash chromatographed [2% (10% conc. NH₄OHin MeOH)/CH₂Cl₂) to afford the free base of the title compound (316.4mg, 91%) The oxalate salt was prepared with an equivalent amount ofoxalic acid in EtOAc. IR (CHCl₃) 3394 cm⁻¹. Ion Spray MS 455.1 (M⁺).[α]_(D)=3.64 (c 0.55, MeOH). C₂₅H₂₇ClN₂O₂S

analysis: calculated found C 65.99 66.17 H  5.98  5.87 N  6.16  6.16

EXAMPLE 33 Preparation of(2S)-3-[4-(5-Chlorobenzo[b]thiophen-2-yl)-2-methyl-1,2,3,6-tetrahydropyridyl]-1-(1H-indol-4-yl)oxy-2-propanolsoxalate

Preparation of4-(5-Chlorobenzo[b]thiophen-2-yl)-2-methyl-1,2,3,6-tetrahydropyridineand4-(5-Chlorobenzo[b]thiophen-2-yl)-2-methyl-1,2,5,6-tetrahydropyridine.

Scheme IA, Step A: A solution of 5-chlorobenzo[b]thiophene (505.4 mg,3.0 mmol) in dry THF (10 mL) at −78° C. is treated with 1.6 M n-BuLi inhexanes (2.2 mL, 3.3 mmol) for 1 h. To this is cannulatedN-t-butoxycarbonyl-4-(2-methyl)piperidone (3.3 mmol) in THF (5 mL) andthe reaction mixture is stirred at −78° C. for 2h, warmed to roomtemperature and stirred for an additional 1 h. The reaction is thenquenched with 40 mL of saturated aqueous NaHCO₃ solution. The mixture isthen extracted with (3×50 mL) EtOAc. The organic layers are washed with40 mL of brine, combined, dried over MgSO₄ and concentrated.Purification with flash chromatography (25% EtOAc/hexanes) affords theintermediate title compound which is carried on to the next step.

Scheme IA, Step B: To a solution ofN-t-butoxycarbonyl-4-(5-chlorobenzo[b]thiophen-2-yl)-4-(2-methyl)piperidinol(2.4 mmol) in dry CH₂Cl₂ (6 mL) at 0° C. is added 3 mL oftrifluoroacetic acid. The resulting solution is stirred at 0° C. for 1.5h. The reaction is then quenched at room temperature with saturatedaqueous NaHCO₃ solution (80 mL). The mixture is extracted with (3×250mL) CH₂Cl₂. The combined organic layers are washed with 150 mL of brineand dried over MgSO₄. The filtrate is then concentrated and the residueis purified and intermediate title compounds partially separated byflash chromatography [8% (10% conc. NH₄OH in MeOH)/CH₂Cl₂]. Ion Spray MS264.0 (M+H)⁺. C₁₄H₁₄ClNS.

Preparation of ( )-cis- and ()-trans-4-(5-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Step C: A solution of4-(5-chlorobenzo[b]thiophen-2-yl)-2-methyl-1,2,3,6-tetrahydropyridineand4-(5-chlorobenzo[b]thiophen-2-yl)-2-methyl-1,2,5,6-tetrahydropyridine(816.8 mg, 3.1 mmol) in 32 mL of 3:1 mixture of ethanol and2,2,2-trifluoroethanol was stirred vigorously at room temperature underhydrogen (balloon pressure) in the presence of 10% Pd/C (820 mg) for 4days. The black slurry was then filtered through a Celite pad to removethe catalyst which was thoroughly washed with THF. The filtrate andwashings were combined, concentrated, and flash chromatographed [8% (10%conc. NH₄OH in MeOH)/CH₂Cl₂] to yield the cis intermediate titlecompound (396.5 mg, 48%) and trans intermediate title compound (220.7mg, 27%).

-   Cis compound: IR (KBr) 3447, 3290 cm⁻¹. Ion Spray MS 266.0 (M+H)⁺.    C₁₄H₁₆ClNS

analysis: calculated found C 63.26 63.04 H  6.07  5.85 N  5.27  5.47

-   Trans compound: IR (KBr) 3434, 3256 cm⁻¹. Ion Spray MS 266.0 (M+H)⁺.    C₁₄H₁₆ClNS

analysis: calculated found C 63.26 63.73 H 6.07 6.52 N 5.27 5.32Preparation of Final Title Compound.

Scheme IV, Step B: A solution of4-(5-chlorobenzo[b]thiophen-2-yl)-2-methyl-1,2,3,6-tetrahydropyridine(123.4 mg, 0.47 mmol) and (S)-4-(oxiranylmethoxy)indole (88.5 mg, 0.47mmol) in MeOH (5 mL) was heated at reflux for 2.5 days. The mixture wasconcentrated and the residue was flash chromatographed [2% (10% conc.NH₄OH in MeOH)/CH₂Cl₂] to afford the free base of the title compound.The oxalate salt was prepared with an equivalent amount of oxalic acidin EtOAc. Ion Spray MS 453 (M)⁺. C₂₅H₂₅ClN₂O₂S.(CO₂H)₂.0.9EtOAc

analysis: calculated found C 59.06 59.34 H 5.54 5.46 N 4.50 4.45

EXAMPLE 34 Preparation of(2S)-3-[4-(5-Chlorobenzo[b]thiophen-2-yl)-2-methyl-1,2,5,6-tetrahydropyridyl]-1-(1H-indol-4-yl)oxy-2-propanolsoxalate

Scheme IV, Step B: A solution of4-(5-chlorobenzo[b]thiophen-2-yl)-2-methyl-1,2,5,6-tetrahydropyridine(147.3 mg, 0.56 mmol, prepared in example 33) and(S)-4-(oxiranylmethoxy)indole (105.7 mg, 0.56 mmol) in MeOH (5 mL) washeated at reflux for 12 hr. The mixture was concentrated and the residuewas flash chromatographed [2% (10% conc. NH₄OH in MeOH)/CH₂Cl₂] toafford the free base of the title compound. The oxalate salt wasprepared with an equivalent amount of oxalic acid in EtOAc (89% yield).IR (KBr) 3402, 1584, 1509, 1502 cm⁻¹. Ion Spray MS 453.0 (M)⁺.C₂₅H₂₅ClN₂O₂S.0.3EtOAc

analysis: calculated found C 65.64 65.61 H 5.76 5.72 N 5.84 5.87

EXAMPLE 35 Preparation of(2S)-(−)-3-[(2R,4R)-4-(5-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate (A) and(2S)-(+)-3-[(2S,4S)-4-(5-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate (B)

Scheme IV, Step B: A solution of ()-cis-4-(5-chlorobenzo[b]thiophen-2-yl)-2-methylpiperidine (390.2 mg,1.47 mmol, prepared in example 33) and (S)-4-(oxiranylmethoxy)indole(277.8 mg, 1.47 mmol) in MeOH (15 mL) was heated at reflux for 30 h. Themixture was concentrated and flash chromotagraphed [2% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to afford the free base to title compound A (309.2 mg,46%) and the free base of title compound B (303.5 mg, 45%). The oxalatesalt of each compound was prepared with an equivalent amount of oxalicacid in EtOAc in quantitative yield.

-   Compound A: IR (KBr) 3406 cm⁻¹. Ion Spray MS 455.0 (M)⁺. [    ]_(D)=−11.93 (c 0.50, MeOH). C₂₅H₂₇ClN₂O₂S.0.8(CO₂H)₂.0.3EtOAc

analysis: calculated found C 60.33 60.51 H 5.65 5.42 N 5.06 4.69

-   Compound B: IR (KBr) 3407 cm⁻¹. Ion Spray MS 455.0 (M)⁺.    [α]_(D)=30.84 (c 0.45, MeOH). C₂₅H₂₇ClN₂O₂S

analysis: calculated found C 65.99 66.15 H 5.98 6.04 N 6.16 5.91

EXAMPLE 36 Preparation of(2S)-3-[(2S,4R)-4-(5-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate (A) and(2S)-(+)-3-[(2R,4S)-4-(5-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate (B)

Scheme IV, Step B: A solution of ()-trans-4-(5-chlorobenzo[b]thiophen-2-yl)-2-methylpiperidine (214.7 mg,0.81 mmol, prepared in example 33) and (S)-4-(oxiranylmethoxy)indole(152.8 mg, 0.81 mmol) in MeOH (10 mL) was heated at reflux for 24 hr.The mixture was concentrated and flash chromotagraphed [2% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to afford the free base of compound A (152.3 mg, 41%) andcompound B (133.7 mg, 36%). The oxalate salt of each compound wasprepared with an equivalent amount of oxalic acid in EtOAc inquantitative yield.

-   Compound A: IR (KBr) 3377 cm⁻¹. Ion Spray MS 455.0 (M)⁺.    [α]_(D)=0.00 (C 0.50, MeOH). C₂₅H₂₇ClN₂O₂S

analysis: calculated found C 65.99 66.0  H  5.98  6.16 N  6.16  6.07

-   Compound B: IR (KBr) 3403 cm⁻¹. Ion Spray MS 455.0 (M)⁺.    [α]_(D)=12.1 (c 0.50, MeOH). C₂₅H₂₇ClN₂O₂S

analysis: calculated found C 65.99 66.21 H 5.98 5.97 N 6.16 6.13

EXAMPLE 37 Preparation of(2S)-(−)-1-(1H-Indol-4-yl)oxy-3-[(2R,4R)-4-(4-methylbenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-2-propanoloxalate (A) and(2S)-(+)-1-(1H-Indol-4-yl)oxy-3-[(2S,4S)-4-(4-methylbenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-2-propanoloxalate (B)

Preparation of ( )-cis-and ()-trans-4-(4-Methylbenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IV, Steps A, B and C: The title compounds were prepared in threesteps in a manner analogous to the procedure described in example 33 toprovide the intermediate title cis-compound (22% in 3 steps) and theintermediate trans-compound (9.7% in three steps). Ion Spray MS 246.1(M+H)⁺.

Preparation of Final Title Compound.

Scheme IV, Step B: A solution of ()-cis-4-(4-methylbenzo[b]thiophen-2-yl)-2-methylpiperidine (200.7 mg,0.82 mmol) and (S)-4-(oxiranylmethoxy)indole (200.7 mg, 0.82 mmol) inMeOH (8 mL) was heated at reflux for 8 h. The mixture was concentratedand flash chromotagraphed [3% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to afford thefree base of compound A (138.9 mg, 39%) and the free base of compound B(159.3 mg, 45%). The oxalate salt of each compound was prepared with anequivalent amount of oxalic acid in EtOAc in quantitative yield.

-   Compound 1: IR (KBr) 3411 cm⁻¹. Ion Spray MS 435.1 (M+H)⁺; 433.1    (M−H)⁺. [α]_(D)=−11.63 (c 0.34, MeOH).    C₂₆H₃₀N₂O₂S.0.9(CO₂H)₂.0.2EtOAc

analysis: calculated found C 64.42 64.52 H 6.31 5.54 N 5.25 4.89

-   Compound 2: IR (KBr) 3414 cm⁻¹. Ion Spray MS 435.1 (M+H)⁺; 433.1    (M−H)⁺. [α]_(D)=20.00 (c 0.50, MeOH).    C₂₆H₃₀N₂O₂S.0.9(CO₂H)₂.0.6EtOAc

analysis: calculated found C 63.80 63.93 H 6.49 6.88 N 4.93 4.72

EXAMPLE 38 Preparation of(2S)-1-(1H-Indol-4-yl)oxy-3-[(2S,4R)-4-(4-methylbenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-2-propanoloxalate (A) and(2S)-(−)-1-(1H-Indol-4-yl)oxy-3-[(2R,4S)-4-(4-methylbenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-2-propanoloxalate (B)

Scheme IV, Step B: A solution of ()-trans-4-(4-methylbenzo[b]thiophen-2-yl)-2-methylpiperidine (88.4 mg,0.36 mmol, prepared in example 37) and (S)-4-(oxiranylmethoxy)indole(71.6 mg, 0.36 mmol) in MeOH (4 mL) was heated at reflux for 6–7 hr. Themixture was concentrated and flash chromotagraphed [2% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to afford the free base of compound A (78.3 mg, 50%) andthe free base of compound B (74.0 mg, 47%). The oxalate salt of eachcompound was prepared with an equivalent amount of oxalic acid in EtOAcin quantitative yield.

-   Compound A: Ion Spray MS 435.0 (M+H)⁺; 433.0 (M−H)⁺. [α]_(D)=0.00 (c    0.28, MeOH). C₂₆H₃₀N₂O₂S.(CO₂H)₂.0.2EtOAc

analysis: calculated found C 63.79 63.57 H 6.25 6.56 N 5.17 4.79

-   Compound B: IR (KBr) 3414 cm⁻¹. Ion Spray MS 435.1 (M+H)⁺; 433.1    (M−H)⁺. [α]_(D)=−13.84 (c 0.29, MeOH). C₂₆H₃₀N₂O₂S.(CO₂H)₂.0.7EtOAc

analysis: calculated found C 63.09 62.71 H 6.46 6.64 N 4.78 4.62

EXAMPLE 39 Preparation of(2S)-(−)-3-[(2R,4R)-4-(4,5-Dimethoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate (A) and(2S)-3-[(2S,4S)-4-(4,5-Dimethoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate (B)

Preparation of ( )-cis- and ()-trans-4-(4,5-Dimethoxybenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Steps A, B and C: The intermediate title compounds wereprepared in 3 steps in a manner analogous to the procedure described inexample 33 to provide the cis-piperidine (61% in 3 steps) andtrans-piperidine (12% in 3 steps). Ion Spray MS 292.0 (M+H)⁺.

Preparation of Final Title Compound.

Scheme IV, Step B: A solution of the ()-cis-4-(4,5-dimethoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (385.7mg, 1.3 mmol) and (S)-4-(oxiranylmethoxy)indole (263.0 mg, 1.3 mmol) inMeOH (13 mL) was heated at reflux for 8 h. The mixture was concentratedand flash chromotagraphed [3% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to afford thefree base of compound A (48.1 mg, 7.6%), free base of compound B (50.8mg, 8.0%), a byproduct (2S)-1-(1H-indol-4-yl)oxy-3-methoxy-2-propanol(153.3 mg, 52%) and recovered cis-piperidine (104.7 mg, 27%). Theoxalate salt of each compound was prepared with an equivalent amount ofoxalic acid in EtOAc in quantitative yield.

-   Compound A: Ion Spray MS 481.0 (M+H)⁺; 479.1 (M−H)⁻. [α]_(D)=−12.93    (c 0.46, MeOH). C₂₇H₃₂N₂O₄S.0.6(CO₂H)₂.0.7EtOAc

analysis: calculated found C 62.44 62.75 H 6.56 6.58 N 4.70 6.36

-   Compound B: Ion Spray MS 481.0 (M+H)⁺; 479.0 (M−H)⁻. [α]_(D)=0.00 (c    0.13, MeOH).

EXAMPLE 40 Preparation of(2S)-(−)-3-[(2S,4R)-4-(4,5-Dimethoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate (A) and(2S)-3-[(2R,4S)-4-(4,5-Dimethoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate (B)

Scheme IV, Step B: A solution of ()-trans-4-(4,5-Dimethoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (82.0mg, 0.28 mmol, prepared in example 39) and (S)-4-(oxiranylmethoxy)indole(55.9 mg, 0.30 mmol) in MeOH (3 mL) was heated at reflux for 6–7 hr. Themixture was concentrated and flash chromotagraphed [2% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to afford the free base of compound A (57.3 mg, 42%) andthe free base of compound B (64.3 mg, 48%). The oxalate salt of eachcompound was prepared with an equivalent amount of oxalic acid in EtOAcin 98 and 88% yield, respectively.

-   Compound A: Ion Spray MS 481.0 (M+H)⁺; 479.0 (M−H)⁻. [α]_(D)=−5.24    (c 0.38, MeOH). C₂₇H₃₂N₂O₄S.0.8(CO₂H)₂.0.5EtOAc

analysis: calculated found C 61.59 61.68 H 6.35 6.13 N 4.36 4.36

-   Compound B: Ion Spray MS 481.0 (M+H)⁺; 479.0 (M−H)⁻. [α]_(D)=0.00 (c    0.37, MeOH). C₂₇H₃₂N₂O₄S.1.0(CO₂H)₂

analysis: calculated found C 61.04 61.07 H 6.01 6.29 N 4.91 4.64

EXAMPLE 41 Preparation of(2S)-(−)-3-[(2R,4R)-[4-(4-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-Indol-4-yl)oxy-2-propanoloxalate (A) and(2S)-3-[(2S,4S)-[4-(4-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-Indol-4-yl)oxy-2-propanoloxalate (B)

Preparation of 4-Chlorobenzo[b]thiophene and 6-Chlorobenzo[b]thiophene.

A mixture of 3-chlorobenzenethiol (9.9 g, 68.5 mmol), K₂CO₃ (11.35 g,82.1 mmol), and bromoacetaldehyde diethyl acetal (8.1 mL, 68.5 mmol) inacetone (250 mL) was stirred at room temperature for 24 h. The base andthe salt formed were removed by filtration with ethereal rinse. Thefiltrate and washings were combined, concentrated, taken up in 250 mL ofEt₂O, and washed with 200 mL each of 0.5 N KOH and brine. The aqueouslayers were back-extracted with 2×250 mL of Et₂O. Combined organiclayers were dried over MgSO₄, concentrated, and dried under vacuum.

To a heated and vigorously stirred biphasic solution of polyphosphoricacid (PPA) (ca. 35 g) and chlorobenzene (350 mL) was added dropwise thecrude acetal in 100 mL of chlorobenzene over 2.5 h period. After heatingat reflux for 1.25 h, the mixture was stirred overnight while allowed tocool to room temperature. The organic layer was separated bydecantation, concentrated, taken up in EtOAc (300 mL), and washed with200 mL each of saturated aqueous NaHCO₃ and brine. The PPA layer wasdissolved in H₂O (ca. 500 mL) and extracted with 3×300 mL of EtOAc whichwas washed with the saturated aqueous NaHCO₃ and brine used above.Combined organic layers were dried over MgSO₄, concentrated, andpurified by PrepLC 500A with hexanes as eluent to yield4-chlorobenzo[b]thiophene (4.269 g, 40%) and 6-chlorobenzo[b]thiophene(5.896 g, 51%) which was contaminated with 3-chlorobenzenedisulfide.FDMS 168(M)⁺.

Preparation of(N-t-Butoxycarbonyl-4-(4-chlorobenzo[b]thiophen-2-yl-2-methyl-4-piperidinol.

Scheme IA, Step A: A solution of 4-chlorobenzo[b]thiophene (1.6315 g,9.67 mmol) in dry THF (20 mL) at −78° C. was treated with 1.6 M n-BuLiin hexanes (7.9 mL, 12.6 mmol) for 1 h. To this was cannulated(N-t-butoxycarbonyl-2-methyl-4-piperidone (420152, 3.2063 g, 15.0 mmol)in THF (15 mL) and the reaction mixture was stirred at −78° C. for 2hand then overnight while allowed to warm to −5° C. The reaction wasquenched with 50 mL of saturated aqueous NaHCO3 solution and the mixturewas extracted with EtOAc (3×100 mL). The organic layers were washed with50 mL of brine, combined, dried over MgSO₄ and concentrated.Purification by PrepLC 500A (0–15% EtOAc/hexanes) afforded unreacted4-chlorobenzo[b]thiophene (1.2646 g, 78%), the intermediate titlecompound (566.9 mg, 15%), and unreacted piperidone (2.4304 g, 76%). IonSpray MS 382 (M+H)⁺.

Preparation of ( )-cis- and ()-trans-4-(4-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Steps B and C: The intermediate title compounds were preparedin two steps from the piperidinol(N-t-butoxycarbonyl-4-(4-chlorobenzo[b]thiophen-2-yl)-2-methyl-4-piperidinolin two steps in a manner analogous to the procedure described in example33: ( )-cis-4-(4-chlorobenzo[b]thiophen-2-yl)-2-methylpiperidine (32%)and ( )-trans-4-(4-chlorobenzo[b]thiophen-2-yl)-2-methylpiperidine (8%).Also obtained was dechlorinated4-(benzo[b]thiophen-2-yl)-2-methylpiperidine (8%). Ion Spray MS 266.0(M+H)⁺.

Preparation of Final Title Compound.

Scheme IV, Step B: The title compounds were prepared in a manneranalogous to the procedure described in example 40 from ()-cis-4-(4-chlorobenzo[b]thiophen-2-yl)-2-methylpiperidine and(S)-4-(oxiranylmethoxy)indole: Compound A (28%) and Compound B (23%).The oxalate salt of each compound was prepared with an equivalent amountof oxalic acid in EtOAc in quantitative yield.

-   Compound A: Ion Spray MS 455.0 (M)⁺; 454.2 (M−H)⁻. [α]_(D)=−13.67 (c    0.44, MeOH). C₂₅H₂₇ClN₂O₂S.1.0(CO₂H)₂.1.0EtOAc

analysis: calculated found C 58.81 58.65 H 5.89 6.27 N 4.42 4.32

-   Compound B: Ion Spray MS 455.0 (M)⁺; 479.0. [α]_(D)=0.00 (c 0.47,    MeOH). C₂₅H₂₇ClN₂O₂S.0.9(CO₂H)₂.1.0EtOAc

analysis: calculated found C 59.27 59.53 H 5.94 6.34 N 4.49 4.51

EXAMPLE 42 Preparation of(2S)-(−)-3-[(2S,4R)-[4-(4-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-Indol-4-yl)oxy-2-propanoloxalate (A) and(2S)-(−)-3-[(2R,4S)-[4-(4-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-Indol-4-yl)oxy-2-propanoloxalate (B)

Scheme IV, Step B: The title compounds were prepared from ()-trans-4-(4-chlorobenzo[b]thiophen-2-yl)-2-methylpiperidine (preparedin example 41) and (S)-4-(oxiranylmethoxy)indole in a manner analogousto the procedure described in example 40: compound A (340%) and compoundB (24%). The oxalate salt of each compound was prepared with anequivalent amount of oxalic acid in EtOAc in quantitative yield.

-   Compound A: Ion Spray MS 455.0 (M)⁺. [α]_(D)=−6.43 (c 0.31, MeOH).    C₂₅H₂₇ClN₂O₂S.1.0(CO₂H)₂.0.7EtOAc

analysis: calculated found C 58.99 58.70 H 5.75 6.10 N 4.62 4.86

-   Compound B: Ion Spray MS 455.0 (M)⁺; 479.0. [α]_(D)=−6.76 (c 0.30,    MeOH). C₂₅H₂₇ClN₂O₂S.1.8(CO₂H)₂.0.9EtOAc

analysis: calculated found C 55.54 55.18 H 5.47 5.84 N 4.02 4.30

EXAMPLE 43 Preparation of(2S)-(−)-3-[(2R,4R)-4-(6-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate (A) and(2S)-(+)-3-[(2S,4S)-4-(6-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate (B).

Preparation ofN-t-Butoxycarbonyl-4-(6-chlorobenzo[b]thiophen-2-yl)-4-piperidinol.

Scheme IA, Step A: A solution of 6-chlorobenzo[b]thiophene (3.3424 g,19.8 mmol, prepared in example 41) in dry THF (90 mL) at −78° C. wastreated with 1.6 M n-BuLi in hexanes (12.5 mL, 20.0 mmol) for 1 h. Tothis was cannulated (N-t-butoxycarbonyl-2-methyl-4-piperidone (420152,2.6672 g, 12.5 mmol) in THF (10 mL) and the reaction mixture was stirredat −78° C. for 3 h. The cold bath was removed and the reaction wasquenched after 10 min with 100 mL of saturated aqueous NaHCO₃ solutionand the mixture was extracted with EtOAc (3×250 mL). The organic layerswere washed with 100 mL of brine, combined, dried over MgSO₄ andconcentrated. Purification by PrepLC 500A (0–30% Et₂O/hexanes) affordedunreacted 6-chlorobenzo[b]thiophene (2.0047 g, 60%)N-t-butoxycarbonyl-4-(4-chlorobenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(0.2528 g, 3.3%, resulted from the 4-chloro contamination in thestarting 6-chlorobenzo[b]thiophene), unreacted piperidone (0.4184 g,16%) and the intermediate title piperidinol (2.7510 g, 36%). Ion SprayMS 382.0 (M+H)⁺.

Preparation of ( )-cis- and ()-trans-4-(4-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Steps B and C: The title compounds were prepared in two stepsfrom N-t-butoxycarbonyl-4-(6-chlorobenzo[b]thiophen-2-yl)-4-piperidinolin a manner analogous to the procedure described in example 33: ()-cis-4-(4-chlorobenzo[b]thiophen-2-yl)-2-methylpiperidine (39%) and ()-trans4-(4-chlorobenzo[b]thiophen-2-yl)-2-methylpiperidine (20%). Alsoobtained was4-(6-chlorobenzo[b]thiophen-2-yl)-2-methyltetrahydropyridines (5%). IonSpray MS 266.0 (M+H)⁺. C₁₄H₁₆ClNS (trans-isomer).

analysis: calculated found C 63.26 63.00 H 6.07 6.21 N 5.27 5.09Preparation of Final Title Compound.

Scheme IV, Step B: The title compounds were prepared from ()-cis-4-(4-chlorobenzo[b]thiophen-2-yl)-2-methylpiperidine and(S)-4-(oxiranylmethoxy)indole in a manner analogous to the proceduredescribed in example 40: Compound A (44%) and compound B (44%). Theoxalate salt of each isomer was prepared with an equivalent amount ofoxalic acid in EtOAc in quantitative yield.

-   Compound A: IR (KBr) 3406, 3350 cm⁻¹. Ion Spray MS 455.0 (M)⁺.    [α]_(D)=−5.28 (c 0.38, MeOH). C₂₅H₂₇ClN₂O₂S.0.1CH₂Cl₂

analysis: calculated found C 65.04 65.03 H 5.92 5.93 N 6.04 5.87

-   Compound B: IR (KBr) 3405 cm⁻¹. Ion Spray MS 455.0 (M)⁺.    [α]_(D)=31.58 (c 0.57, MeOH). C₂₅H₂₇ClN₂O₂S

analysis: calculated found C 65.99 65.99 H 5.98 5.97 N 6.16 5.89

EXAMPLE 44 Preparation of(2S)-3-[(2S,4R)-4-(6-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate (A) and(2S)-(+)-3-[(2R,4S)-4-(6-Chlorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate (B)

Scheme IV, Step B: The title compounds were prepared from ()-trans-4-(4-chlorobenzo[b]thiophen-2-yl)-2-methylpiperidine (preparedin example 43) and (S)-4-(oxiranylmethoxy)indole in a manner analogousto the procedure described in example 43: Compound A (42%) and compoundB (42%). The oxalate salt of each compound was prepared with anequivalent amount of oxalic acid in EtOAc in quantitative yield.

-   Compound A: [α]_(D) (could not be determined due to solubility    problem). IR (KBr) 3406 cm⁻¹. Ion Spray MS 455.0 (M)⁺. C₂₅H₂₇ClN₂O₂S

analysis: calculated found C 65.99 66.22 H 5.98 5.74 N 6.16 5.86

-   Compound B: IR (KBr) 3406 cm⁻¹ . Ion Spray MS 455.0 (M)⁺.    [α]_(D)=+10.19 (c 0.59, MeOH). C₂₅H₂₇ClN₂O₂S.0.8(CO₂H)₂.0.7EtOAc

analysis: calculated found C 59.98 60.03 H 5.86 6.04 N 4.76 4.37

EXAMPLE 45 Preparation of(2S)-(−)-1-(1H-Indol-4-yl)oxy-3-[(2R,4R)-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-2-propanoloxalate

Preparation ofN-t-Butoxycarbonyl-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol.

Scheme IA, Step A: To a solution of 6-methoxybenzo[b]thiophene (1.93 g,11.7 mmol) in dry THF (55 mL) at −78° C. was added 1.6 M n-BuLi inhexanes (8.06 mL, 12.9 mmol). The solution was stirred at −78° C. for 45min. N-t-Butoxycarbonyl-2-methyl-4-piperidone (1.50 g, 7.03 mmol)dissolved in THF (40 mL) was added via a cannula at −78° C. The reactionmixture was stirred at −78° C. for 3 h. The reaction was then quenchedwith 55 mL of saturated aqueous NH₄Cl solution. The mixture wasextracted (1×400 mL) with EtOAc. The combined organic layers were thendried over MgSO₄ and filtered. The filtrate was concentrated andpurified by medium pressure chromatography (20% EtOAc/hexanes) to givethe intermediate title compound as a white foam (1.82 g, 69%). IR (KBr)3422 (br), 1690, 1666 cm⁻¹ . FDMS m/e=378 (M⁺).

Preparation of(±)-cis-4-(6-Methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(1.80 g, 4.77 mmol) in dry CH₂Cl₂ (14 mL) at 0° C. was added 6 mL oftrifluoroacetic acid. The resulting purple solution was stirred at 0° C.for 1.5 h. The reaction was then quenched at room temperature withsaturated aqueous NaHCO₃ solution (150 mL). The mixture was extracted(1×300 mL) with CH₂Cl₂. The combined organic layers were dried overMgSO₄ and concentrated to yield 1.13 g of crude regioisomeric olefins.To a solution of the crude olefins (1.13 g) in a 3:1 mixture of ethanol(36 mL) and 2,2,2-trifluoroethanol (12 mL) was added 10% Pd/C (1.30 g).The black slurry was stirred vigorously at room temperature underhydrogen (balloon pressure) for 9 days. The black slurry was thenfiltered over a pad of diatomaceous earth and washed with ethanol. Thefiltrate was then concentrated, and the residue was purified by silicagel chromatography [6.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to provide theintermediate title compound as a light brown solid (0.461 g, 40%). mp(oxalate) 248–250° C. Ion Spray MS 262 (M+H)⁺.

Preparation of(±)-trans-4-(6-Methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(1.80 g, 4.77 mmol) in dry CH₂Cl₂ (14 mL) at 0° C. was added 6 mL oftrifluoroacetic acid. The resulting purple solution was stirred at 0° C.for 1.5 h. The reaction was then quenched at room temperature withsaturated aqueous NaHCO₃ solution (150 mL). The mixture was extracted(1×300 mL) with CH₂Cl₂. The combined organic layers were dried overMgSO₄ and concentrated to yield 1.13 g of crude regioisomeric olefins.To a solution of the crude olefins (1.13 g) in a 3:1 mixture of ethanol(36 mL) and 2,2,2-trifluoroethanol (12 mL) was added 10% Pd/C (1.30 g).The black slurry was stirred vigorously at room temperature underhydrogen (balloon pressure) for 9 days. The black slurry was thenfiltered over a pad of diatomaceous earth and washed with ethanol. Thefiltrate was then concentrated, and the residue was purified by silicagel chromatography [6.5% 2.0 M NH₃ in MeOH)/CH₂Cl₂] to give(±)-trans-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine as alight brown oil (0.257 g, 23%). Ion Spray MS 262 (M+H)⁺.

Preparation of Final Title Compound.

Scheme IV, Step B: A solution of(±)-cis-2-methyl-4-(6-methoxybenzo[b]thiophen-2-yl)piperidine (0.200 g,0.765 mmol) and (S)-4-(oxiranylmethoxy)indole (0.145 g, 0.765 mmol) inMeOH (10 mL) was heated at reflux for 28 h and then cooled andevaporated. The residue was purified using silica gel chromatography [1%(2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base of the final titlecompound as a white foam (0.133 g, 39%). The oxalate salt was preparedwith 1 equiv. of oxalic acid in EtOAc. mp 124–127° C. IR (KBr) 3406,3350 (br) cm⁻¹. Ion Spray MS 451 (M+H)⁺; 449 (M−H)⁻; 509 (M+CH₃COO⁻)⁻.[α]_(D) =−4.25 (c 0.47, MeOH). C₂₆H₃₀N₂O₃S

analysis: calculated found C 69.30 69.47 H 6.71 6.62 N 6.22 6.07

EXAMPLE 46 Preparation of(2S)-(+)-1-(1H-indol-4-yl)oxy-3-[(2S,4S)-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-2-methyl-4-(6-methoxybenzo[b]thiophen-2-yl)piperidine (0.200 g,0.765 mmol, prepared in example 45) and (S)-4-(oxiranylmethoxy)indole(0.145 g, 0.765 mmol) in MeOH (10 mL) was heated at reflux for 28 h andthen cooled and evaporated. The residue was purified using silica gelchromatography [1% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the titlecompound as a white foam (0.087 g, 25%). The oxalate salt was preparedwith 1 equiv. of oxalic acid in EtOAc. mp 119–121° C. IR (KBr) 3411,3350 (br) cm⁻¹. Ion Spray MS 451 (M+H)⁺; 449 (M−H)⁻; 509 (M+CH₃COO⁻)⁻.[α]D =7.68 (c 0.52, MeOH). C₂₆H₃₀N₂O₃S

analysis: calculated found C 69.30 69.50 H 6.71 6.71 N 6.22 6.22

EXAMPLE 47 Preparation of(2S)-1-(1H-Indol-4-yl)oxy-3-[(2S,4R)-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-2-propanol

Scheme IV, Step B: A solution of(±)-trans-2-methyl-4-(6-methoxybenzo[b]thiophen-2-yl)piperidine (0.200g, 0.765 mmol, prepared in example 45) and (S)-4-(oxiranylmethoxy)indole(0.145 g, 0.765 mmol) in MeOH (10 mL) was heated at reflux for 26 h andthen cooled. The reaction mixture was filtered and washed with MeOH togive the title compound as a white solid (0.138.1 g, 40%). mp 179–182°C. IR (KBr) 3355 (br) cm⁻¹. Ion Spray MS 451 (M+H)⁺; 449 (M−H)⁻; 509(M+CH₃COO⁻)⁻. [α]_(D) =0 (c 0.44, DMSO). C₂₆H₃₀N₂O₃S

analysis: calculated found C 69.30 69.28 H 6.71 6.54 N 6.22 6.18

EXAMPLE 48 Preparation of(2S)-(+)-1-(1H-Indol-4-yl)oxy-3-[(2R,4S)-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-2-methyl-4-(6-methoxybenzo[b]thiophen-2-yl)piperidine (0.200g, 0.765 mmol) and (S)-4-(oxiranylmethoxy)indole (0.145 g, 0.765 mmol)in MeOH (10 mL) was heated at reflux for 26 h and then cooled andfiltered. The filtrate was concentrated and purified using silica gelchromatography [2% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a white foam (0.136 g, 39%). The oxalate salt wasprepared with 1 equiv. of oxalic acid in EtOAc. mp 66–68° C. IR (KBr)3403, 3350 (br) cm⁻¹. Ion Spray MS 451 (M+H)⁺; 449 (M−H)⁻; 509(M+CH₃COO⁻)⁻. [α]_(D)=11.27 (c 0.36, MeOH). C₂₆H₃₉N₂O₃S

analysis: calculated found C 69.30 69.17 H 6.71 6.42 N 6.22 6.08

EXAMPLE 49 Preparation of(2S)-(−)-1-(1H-Indol-4-yl)oxy-3-[(2R,4R)-2-methyl-4-(4-trifluoromethylbenzo[b]thiophen-2-yl)piperidinyl]-2-propanoloxalate

Preparation ofN,N-Dimethyl-2-hydroxy-2-(2-trifluoromethylphenyl)thioacetamide.

To a solution of lithium diisopropylamide (2.0 M in heptane) (34.5 mL,68.9 mmol) in 100 mL of dry THF (100 mL) cooled to −78° C. was added2-trifluoromethylbenzaldehyde (7.58 mL, 57.4 mmol) andN,N-dimethylthioformamide (4.89 mL, 57.4 mmol) dissolved in 150 mL ofdry THF via a cannula over a period of 10 min. The reaction mixture wasstirred at −78° C. for 15 min, then warmed to 0° C., and quenched withsaturated aqueous NH₄Cl solution (300 mL). The mixture was extractedwith (3×1.0 L) with EtOAc. The combined organic layers were dried overMgSO₄ and concentrated. The residue was purified by medium pressurechromatography (silica gel, 25% EtOAc/hexanes) and then recrystallizedfrom EtOAc/hexanes to give the intermediate title compound as anoff-white solid (3.18 g, 21%). mp 112–115° C. IR (KBr) 3350 (br), 3239cm⁻¹. Ion Spray MS 264 (M+H)⁺; 246 (M−H₂O)⁺; 322 (M+CH₃COO⁻)⁻.

Preparation of 2-Dimethylamino-4-trifluoromethylbenzo[b]thiophene.

N,N-Dimethyl-2-hydroxy-2-(2-trifluoromethylphenyl)thioacetamide (3.18 g,12.1 mmol) was dissolved in Eaton's reagent (7.5% w/wP₂O₅/methanesulfonic acid) (21.2 mL). The reaction mixture was heated to80° C. and stirred for 45 min. The reaction was quenched by pouring thereaction mixture slowly into cooled (0° C.) 5.0 N NaOH (75 mL). Themixture was extracted (2×300 mL) with EtOAc. The combined organic layerswere dried over MgSO₄, concentrated, and the residue was purified bymedium pressure chromatography (8% Et₂O/hexanes) to give theintermediate title compound as a yellow solid (0.816 g, 28%). mp 70–73°C. Ion Spray MS 246 (M+H)⁺.

Preparation of 4-Trifluoromethylthianapthen-2-one.

2-Dimethylamino-4-trifluoromethylbenzo[b]thiophene (0.795 g, 3.24 mmol)was dissolved in a 1:1 mixture of THF/1.0 N HCl (30 mL). The biphasicmixture was stirred vigorously and heated at reflux for 4.5 days. Thereaction mixture was then cooled to room temperature and the layers wereseparated. The aqueous layer was extracted (2×100 mL) with Et₂O. Thecombined organic layers were dried over MgSO₄ and concentrated. Theresidue was then purified by silica gel chromatography (1% Et₂O/hexanes)to give the intermediate title compound as a yellow oil (0.528 g, 75%).IR (CHCl₃) 1720 cm⁻¹. Ion Spray MS 217 (M−H)⁻.

Preparation of 4-Trifluoromethylbenzo[b]thiophene.

To a solution of 4-trifluoromethylthianapthen-2-one (0.509 g, 2.33 mmol)in CH₂Cl₂ (23 mL) was added dropwise 1.0 M diisobutylaluminum hydride intoluene (2.57 mL, 2.57 mmol) at 0° C. The solution was stirred at 0° C.for 15 min. The reaction was quenched with conc. HCl (15 mL). Thismixture was then stirred vigorously for 2 h. The layers were separated,and the organic layer was dried over MgSO₄, concentrated, and theresidue was purified by silica gel chromatography (100% hexanes) to givethe intermediate title compound as a clear liquid (0.300 g, 65%). IR(CHCl₃) 1313 cm⁻¹. FDMS m/e=216 (M+14)⁺;

Preparation ofN-t-Butoxycarbonyl-2-methyl-4-(4-trifluoromethylbenzo[b]thiophen-2-yl)-4-piperidinol.

Scheme IA, Step A: To a solution of 4-trifluoromethylbenzo[b]thiophene(0.440 g, 2.18 mmol) in dry THF (10 mL) at −78° C. was added 1.6 Mn-BuLi in hexanes (1.50 mL, 2.39 mmol). The solution was stirred at −78°C. for 30 min. N-t-Butoxycarbonyl-2-methyl-4-piperidone (0.464 g, 2.18mmol) dissolved in THF (5 mL) was added via a cannula at −78° C. Thereaction mixture was warmed to room temperature over 18 h. The reactionwas then quenched with 50 mL of saturated aqueous NH₄Cl solution. Themixture was extracted (3×100 mL) with EtOAc. The combined organic layerswere then dried over MgSO₄, concentrated and purified by silica gelchromatography (10% EtOAc/hexanes) to give the intermediate titlecompound as a white foam (0.617 g, 68%). IR (KBr) 3416 (br), 1663 cm⁻¹.Ion Spray MS 416 (M+H)⁺; 298 (M−(BOC+H₂O))⁺; 342 (M−73)⁺ (base peak);890 (2M+CH₃COO).

Preparation of(±)-trans-4-Hydroxy-2-methyl-4-(4-trifluoromethylbenzo[b]thiophen-2-yl)piperidine.

Scheme IC: To a solution ofN-t-butoxycarbonyl-2-methyl-4-(4-trifluoromethylbenzo[b]thiophen-2-yl)-4-piperidinol(0.611 g, 1.47 mmol) in dry CH₂Cl₂ (5 mL) at 0° C. was added 2 mL oftrifluoroacetic acid. The resulting brown solution was stirred at 0° C.for 2 h. The reaction was then quenched at room temperature withsaturated aqueous NaHCO₃ solution (30 mL). The mixture was extracted(1×60 mL) with CH₂Cl₂. The combined organic layers were dried over MgSO₄and concentrated to yield 0.418 g of the crude deprotected product. To asolution of the piperidine (0.418 g) in a 3:1 mixture of ethanol (12 mL)and 2,2,2-trifluoroethanol (4 mL) was added 10% Pd/C (0.450 g). Theblack slurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 6 h. The black slurry was then filtered over apad of diatomaceous earth and washed with ethanol. The filtrate was thenconcentrated, and the residue was purified by silica gel chromatography[7% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the intermediate title compoundas a white foam (0.127 g, 27%). mp 182–184° C. IR (KBr) 3300 (br), 3150(br) cm⁻¹. Ion Spray MS 316 (M+H)⁺; 298 (M−H₂O)⁺.

Preparation of(±)-trans-2-Methyl-4-(4-trifluoromethylbenzo[b]thiophen-2-yl)piperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl-2-methyl-4-(4-trifluoromethylbenzo[b]thiophen-2-yl)-4-piperidinol(0.611 g, 1.47 mmol) in dry CH₂Cl₂ (5 mL) at 0° C. was added 2 mL oftrifluoroacetic acid. The resulting brown solution was stirred at 0° C.for 2 h. The reaction was then quenched at room temperature withsaturated aqueous NaHCO₃ solution (30 mL). The mixture was extracted(1×60 mL) with CH₂Cl₂. The combined organic layers were dried over MgSO₄and concentrated to yield 0.418 g of the crude deprotected product. To asolution of the piperidine (0.418 g) in a 3:1 mixture of ethanol (12 mL)and 2,2,2-trifluoroethanol (4 mL) was added 10% Pd/C (0.450 g). Theblack slurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 6 h. The black slurry was then filtered over apad of diatomaceous earth and washed with ethanol. The filtrate was thenconcentrated and the residue was purified by silica gel chromatography[7% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the intermediate title compoundas an off-white foam (0.044 g, 10%). Ion Spray MS 300 (M+H)⁺.

Preparation of(±)-cis-2-Methyl-4-(4-trifluoromethylbenzo[b]thiophen-2-yl)piperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl-2-methyl-4-(4-trifluoromethylbenzo[b]thiophen-2-yl)-4-piperidinol(0.611 g, 1.47 mmol) in dry CH₂Cl₂ (5 mL) at 0° C. was added 2 mL oftrifluoroacetic acid. The resulting brown solution was stirred at 0° C.for 2 h. The reaction was then quenched at room temperature withsaturated aqueous NaHCO₃ solution (30 mL). The mixture was extracted(1×60 mL) with CH₂Cl₂. The combined organic layers were dried over MgSO₄and concentrated to yield 0.418 g of the crude deprotected product. To asolution of the piperidine (0.418 g) in a 3:1 mixture of ethanol (12 mL)and 2,2,2-trifluoroethanol (4 mL) was added 10% Pd/C (0.450 g). Theblack slurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 6 h. The black slurry was then filtered over apad of diatomaceous earth and washed with ethanol. The filtrate was thenconcentrated and the residue was purified by silica gel chromatography[7% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the intermediate title compoundas an off-white foam (0.140 g, 32%). mp 106–108° C. IR (KBr) 3400 (br),3228 cm⁻¹. Ion Spray MS 300 (M+H)⁺.

Preparation of Final Title Compound.

Scheme IV, Step B: A solution of(±)-cis-2-methyl-4-(4-trifluoromethylbenzo[b]thiophen-2-yl)piperidine(0.133 g, 0.444 mmol) and (S)-4-(oxiranylmethoxy)indole (0.084 g, 0.444mmol) in MeOH (7 mL) was heated at reflux for 26 h and then cooled andevaporated. The residue was purified using silica gel chromatography[1.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base of the finaltitle compound as a white foam (0.101 g, 47%). The oxalate salt wasprepared with 1 equiv. of oxalic acid in EtOAc. mp (oxalate) 102–105° C.IR (KBr) 3407, 3350 (br) cm⁻¹. Ion Spray MS 489 (M+H)⁺; 487 (M−H)⁻.[α]_(D)=−7.19 (c 0.56, MeOH). C₂₆H₂₇F₃N₂O₂S

analysis: calculated found C 63.92 63.67 H 5.57 5.79 N 5.73 5.76

EXAMPLE 50 Preparation of(2S)-(+)-1-(1H-Indol-4-yl)oxy-3-[(2S,4S)-2-methyl-4-(4-trifluoromethylbenzo[b]thiophen-2-yl)piperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-2-methyl-4-(4-trifluoromethylbenzo[b]thiophen-2-yl)piperidine(0.133 g, 0.444 mmol, prepared in example 49) and(S)-4-(oxiranylmethoxy)indole (0.084 g, 0.444 mmol) in MeOH (7 mL) washeated at reflux for 26 h and then cooled and evaporated. The residuewas purified using silica gel chromatography [1.5% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the title compound as a whitefoam (0.090 g, 41%). The oxalate salt was prepared with 1 equiv. ofoxalic acid in EtOAc. mp (oxalate) 115–119° C. IR (KBr) 3407, 3350 (br)cm⁻¹. Ion Spray MS 489 (M+H)⁺; 487 (M−H)⁻; 547 (M+CH₃COO⁻)⁻.[α]_(D)=6.10 (c 0.33, MeOH). C₂₆H₂₇F₃N₂O₂S

analysis: calculated found C 63.92 63.73 H 5.57 5.46 N 5.73 5.49

EXAMPLE 51 Preparation of(2S)-1-(1H-Indol-4-yl)oxy-3-[(2S,4R)-2-methyl-4-(4-trifluoromethylbenzo[b]thiophen-2-yl)piperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-2-methyl-4-(4-trifluoromethylbenzo[b]thiophen-2-yl)piperidine(0.040 g, 0.132 mmol, prepared in example 49) and(S)-4-(oxiranylmethoxy)indole (0.025 g, 0.132 mmol) in MeOH (2 mL) washeated at reflux for 19 h and then cooled and evaporated. The residuewas purified using silica gel chromatography [1.5% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the title compound as anoff-white foam (0.022 g, 34%). The oxalate salt was prepared with 1equiv. of oxalic acid in EtOAc. mp (oxalate) 82–26° C. Ion Spray MS 489(M+H)⁺; 487 (M−H)⁻; 547 (M+CH₃COO⁻)⁻. C₂₆H₂₇F₃N₂O₂S.0.2CH₂Cl₂

analysis: calculated found C 62.24 62.52 H 5.46 5.72 N 5.54 5.20

EXAMPLE 52 Preparation of(2S)-1-(1H-Indol-4-yl)oxy-3-[(2R,4S)-2-methyl-4-(4-trifluoromethylbenzo]b]thiophen-2-yl)piperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-2-methyl-4-(4-trifluoromethylbenzo[b]thiophen-2-yl)piperidine(0.040 g, 0.132 mmol, prepared in example 49) and(S)-4-(oxiranylmethoxy)indole (0.025 g, 0.132 mmol) in MeOH (2 mL) washeated at reflux for 19 h and then cooled and evaporated. The residuewas purified using silica gel chromatography [1.5% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the title compound as anoff-white foam (0.023 g, 35%). The oxalate salt was prepared with 1equiv. of oxalic acid in EtOAc. mp (oxalate) 83–87° C. Ion Spray MS 489(M+H)⁺; 487 (M−H)⁻. C₂₆H₂₇F₃N₂O₂S.0.3C₆H₁₄

analysis: calculated found C 64.91 65.00 H 6.11 6.15 N 5.45 5.15

EXAMPLE 53 Preparation of(2S)-3-[(2R,4S)-4-Hydroxy-2-methyl-4-(4-trifluoromethylbenzo[b]thiophen-2-yl)piperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-hydroxy-2-methyl-4-(4-trifluoromethylbenzo[b]thiophen-2-yl)piperidine(0.106 g, 0.336 mmol, prepared in example 49) and(S)-4-(oxiranylmethoxy)indole (0.064 g, 0.336 mmol) in MeOH (5 mL) washeated at reflux for 24 h and then cooled and evaporated. The residuewas purified using silica gel chromatography [4% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the title compound as a whitefoam (0.061 g, 36%). The oxalate salt was prepared with 1 equiv. ofoxalic acid in EtOAc. mp (oxalate) 110° C. (dec.). IR (KBr) 3405, 3350(br) cm⁻¹. Ion Spray MS 505 (M+H)⁺; 487 (M−H₂O)⁺; 503 (M−H)⁻; 563(M+CH₃COO⁻)⁻. [α]_(D)=0 (c 0.34, MeOH). C₂₆H₂₇F₃N₂O₃S.C₂H₂O₄

analysis: calculated found C 56.56 56.32 H 4.92 5.14 N 4.71 4.46

EXAMPLE 54 Preparation of(2S)-3-[(2S,4R)-4-Hydroxy-2-methyl-4-(4-trifluoromethylbenzo[b]thiophen-2-yl)piperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-hydroxy-2-Methyl-4-(4-trifluoromethylbenzo[b]thiophen-2-yl)piperidine(0.106 g, 0.336 mmol, prepared in example 49) and(S)-4-(oxiranylmethoxy)indole (0.064 g, 0.336 mmol) in MeOH (5 mL) washeated at reflux for 24 h and then cooled and evaporated. The residuewas purified using silica gel chromatography [4% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the title compound as a whitefoam (0.066 g, 39%). The oxalate salt was prepared with 1 equiv. ofoxalic acid in EtOAc. mp (oxalate) 103–105° C. IR (KBr) 3404, 3350 (br)cm⁻¹. Ion Spray MS 505 (M+H)⁺; 487 (M−H₂O)⁺; 503 (M−H)⁻; 563(M+CH₃COO⁻)⁻. [α]_(D)=−5.19 (c 0.39, MeOH). C₂₆H₂₇F₃N₂O₃S.C₂H₂O₄

analysis: calculated found C 56.56 56.39 H 4.92 5.04 N 4.71 4.43

EXAMPLE 55 Preparation of(2S)-3-[4-(4-Fluorobenzo[b]thiophen-2-yl)piperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Preparation of 3-Fluorobenzenethioacetaldehyde diethyl acetal.

The title compound was prepared in 95% crude yield from3-flourobenzenethiol in a manner analogous to the procedure of Graham,S. L., et. al. J. Med. Chem. 1989,32, 2548–2554.

Preparation of 4- and 6-Fluorobenzo[b]thiophene.

To a biphasic mixture of polyphosphoric acid (PPA; 22.5 g) and 210 mL ofdry chlorobenzene heated to reflux was added dropwise3-fluorobenzenethioacetaldehyde diethyl acetal (10.0 g, 40.9 mmol) in 40mL of chlorobenzene over a period of 45 min. The dark green biphasicmixture was heated at reflux for an additional hour. The reactionmixture was cooled to room temperature and the organic layer wasdecanted off the PPA layer. The PPA layer was cooled to 0° C. anddiluted with 200 mL of H₂O. This aqueous layer was extracted; withCH₂Cl₂ (2×400 mL). The combined organic layers dried over MgSO₄ andconcentrated under reduced pressure. The residue was purified by mediumpressure chromatography to give 4- and 6-fluorobenzo[b]thiophene as agreen oil (5.12 g, 82%). FDMS m/e=152 (M⁺).

Preparation ofN-t-Butoxycarbonyl-4-(4-fluorobenzo[b]thiophen-2-yl)-4-piperidinol.

Scheme IA, Step A: To a solution of 4- and 6-fluorobenzo[b]thiophene(1.70 g, 11.2 mmol) in dry THF (50 mL) at −78° C. was added 1.6 M n-BuLiin hexanes (9.08 mL, 14.5 mmol). The solution was stirred at −78° C. for35 min. N-t-butoxycarbonyl-4-piperidone (2.67 g, 15.6 mmol) dissolved inTHF (10 mL) was added via a cannula at −78° C. The reaction mixture waskept at −78° C. for 1.5 h, then allowed to warm to room temperature. Thereaction was quenched with 150 mL of saturated aqueous NH₄Cl solution.The mixture was then extracted (3×300 mL) with EtOAc. The combinedorganic layers were dried over MgSO₄ and filtered. The filtrate wasconcentrated and purified by medium pressure chromatography (silica gel,20% EtOAc/hexanes) to give the intermediate title compound as a whitefoam (0.525 g, 13%). IR (CHCl₃) 3350 (br), 1683, 1244 cm⁻¹. Ion Spray MS352 (M+H)⁺; 234 (M−(BOC+H₂0)⁺; 278 (M−73)⁺ (base peak); 410(M+CH₃COO⁻)⁻.

Preparation of4-(4-Fluorobenzo[b]thiophen-2-yl)-1,2,5,6-tetrahydropyridine.

Scheme IA, Step B: To a solution ofN-t-butoxycarbonyl-4-(4-fluorobenzo[b]thiophen-2-yl)-4-piperidinol(0.507 g, 1.44 mmol) in dry CH₂Cl₂ (5 mL) at 0° C. was added 2 mL oftrifluoroacetic acid. The solution was stirred at 0° C. for 1.5 h. Thereaction was then quenched at room temperature with saturated aqueousNaHCO₃ solution (25 mL). The mixture was extracted (3×50 mL) withCH₂Cl₂. The combined organic layers were dried over MgSO₄ andconcentrated to give the intermediate title compound as a brownsemi-solid (0.316 g, 94% (crude)). mp 83–86° C. Ion Spray MS 234 (M+H)⁺.

Preparation of 4-(4-Fluorobenzo[b]thiophen-2-yl)piperidine.

Scheme IA, Step C: To a solution of4-(4-fluorobenzo[b]thiophen-2-yl)-1,2,5,6-tetrahydropyridine (0.239 g,1.03 mmol) in a 3:1 mixture of ethanol (9 mL) and 2,2,2-trifluoroethanol(3 mL) was added 10% Pd/C (0.250 g). The black slurry was stirredvigorously at room temperature under hydrogen (balloon pressure) for 8h. The black slurry was then filtered over a pad of diatomaceous earthand washed with ethanol. The filtrate was concentrated, and the residuewas purified by silica gel chromatography [8% (10% conc. NH₄OH inMeOH)/CH₂Cl₂] to give the intermediate title compound as a yellowsemi-solid (0.127 g, 53%). IR (KBr) 3432 (br), 3252, 3216, 1234 cm⁻¹.Ion Spray MS 236 (M+H)⁺.

Preparation of Final Title Compound.

Scheme IV, Step B: A solution of4-(4-fluorobenzo[b]thiophen-2-yl)piperidine (0.021 g, 0.089 mmol) and(2S)-4-glycidyloxy-2-methylindole (0.018 g, 0.089 mmol) in MeOH (2 mL)was heated at reflux for 6 h and then cooled and evaporated. The residuewas purified using silica gel chromatography [2% (10% conc. NH₄OH inMeOH)/CH₂Cl₂] to give the free base of the final title compound as anoff-white foam (0.029 g, 73%). The oxalate salt was prepared with 1equiv. of oxalic acid in EtOAc. mp (oxalate) 156–159° C. (dec.). IonSpray MS 439 (M+H)⁺; 437 (M−H)⁻; 497 (M+CH₃COO⁻)⁻. C₂₅H₂₇FN₂O₂S.C₂H₂O₄

analysis: calculated found C 61.35 61.17 H 5.53 5.29 N 5.30 5.01

EXAMPLE 56 Preparation of(2S)-3-[(2R,4R)-4-(4-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate

Preparation ofN-t-Butoxycarbonyl-4-(4-fluorobenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol.

Scheme IA, Step A: To a solution of 4- and 6-fluorobenzo[b]thiophene(12.4 g, 81.7 mmol, prepared in example 55) in dry THF (415 mL) at −78°C. was added 1.6 M n-BuLi in hexanes (56.4 mL, 90.2 mmol). The solutionwas stirred at −78° C. for 1.5 h.N-t-butoxycarbonyl-2-methyl-4-piperidone (15.7 g, 73.5 mmol) dissolvedin THF (40 mL) was added via a cannula at −78° C. The reaction mixturewas stirred at −78° C. for 4 h. The reaction was then quenched with 300mL of saturated aqueous NH₄Cl solution. The mixture was extracted (2×500mL) with EtOAc. The combined organic layers were then dried over MgSO₄and filtered. The filtrate was concentrated and purified by mediumpressure chromatography (15% EtOAc/hexanes) to give the title compoundas a white foam (3.66 g, 14%). ¹HNMR (CDCl₃) 7.54 (d, J=8.8 Hz, 1H),7.25 (s, 1H), 7.22 (m, 1H), 6.96 (dd, J=9.0, 8.1, 1H), 4.31 (dist t,1H), 3.85 (m, 1H), 3.18 (dt, J=13.0, 2.9 Hz, 1H), 2.02–1.82 (m, 1H),1.64 (dd, J=14.2, 6.8, 1H), 1.54–1.44 (m, 11H), 1.28 (d, J=6.8 Hz, 3H)

Preparation of(±)-cis4-(4-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-(4-fluorobenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(1.47 g, 4.02 mmol) in dry CH₂Cl₂ (12 mL) at 0° C. was added 5 mL oftrifluoroacetic acid. The solution was stirred at 0° C. for 2 h. Thereaction was then quenched at room temperature with saturated aqueousNaHCO₃ solution (70 mL). The mixture was extracted (2×150 mL) withCH₂Cl₂. The combined organic layers were dried over MgSO₄ andconcentrated to yield 0.880 g of the crude regioisomeric olefins. To asolution of the crude olefins (0.880 g) in a 3:1 mixture of ethanol (30mL) and 2,2,2-trifluoroethanol (10 mL) was added 10% Pd/C (0.900 g). Theblack slurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 15 h. The black slurry was then filtered over apad of diatomaceous earth and washed with ethanol. The filtrate wasconcentrated, and the residue was purified by silica gel chromatography[7% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the intermediate title compoundas a white solid (0.227 g, 23%). mp 63–65° C. Ion Spray MS 251 (M+2H)⁺.

Preparation of(±)-trans-4-(4-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-(4-fluorobenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(1.47 g, 4.02 mmol) in dry CH₂Cl₂ (12 mL) at 0° C. was added 5 mL oftrifluoroacetic acid. The solution was stirred at 0° C. for 2 h. Thereaction was then quenched at room temperature with saturated aqueousNaHCO₃ solution (70 mL). The mixture was extracted (2×150 mL) withCH₂Cl₂. The combined organic layers were dried over MgSO₄ andconcentrated to yield 0.880 g of the crude regioisomeric olefins. To asolution of the crude olefins (0.880 g) in a 3:1 mixture of ethanol (30mL) and 2,2,2-trifluoroethanol (10 mL) was added 10% Pd/C (0.900 g). Theblack slurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 15 h. The black slurry was then filtered over apad of diatomaceous earth and washed with ethanol. The filtrate wasconcentrated, and the residue was purified by silica gel chromatography[7% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the intermediate title compoundas a white solid (0.128 g, 13%). Ion Spray MS 250 (M+H)⁺.

Preparation of Final Title Compound.

Scheme IV, Step B: A solution of(±)-cis-4-(4-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.068 g,0.273 mmol) and (S)-4-(oxiranylmethoxy)indole (0.052 g, 0.273 mmol) inMeOH (4 mL) was heated at reflux for 22 h and then cooled andevaporated. The residue was purified using silica gel chromatography[1–1.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂) to provide the free base of thefinal title compound as a white foam (0.046 g, 38%). The oxalate saltwas prepared with 1 equiv. of oxalic acid in EtOAc. IR (KBr) 3407, 3300(br), 1237 cm⁻¹. Ion Spray MS 439 (M+H)⁺; 437 (M−H)⁻; 497 (M+CH₃COO⁻)⁻.C₂₅H₂₇FN₂O₂S

analysis: calculated found C 68.47 68.68 H 6.21 6.40 N 6.39 6.48

EXAMPLE 57 Preparation of(2S)-3-[(2S,4S)-4-(4-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(4-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.068 g,0.273 mmol, prepared in example 56) and (S)-4-(oxiranylmethoxy)indole(0.052 g, 0.273 mmol) in MeOH (4 mL) was heated at reflux for 22 h andthen cooled and evaporated. The residue was purified using silica gelchromatography [1–1.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free baseof the title compound as a white foam (0.048 g, 40%). The oxalate saltwas prepared with 1 equiv. of oxalic acid in EtOAc. IR (KBr) 3406, 3300(br), 1237 cm⁻¹. Ion Spray MS 439 (M+H)⁺; 437 (M−H)⁻. C₂₅H₂₇FN₂O₂S

analysis: calculated found C 68.47 68.37 H 6.21 6.41 N 6.39 6.45

EXAMPLE 58 Preparation of(2S)-3-[(2S,4R)-4-(4-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(4-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.123 g,0.494 mmol, prepared in example 56) and (S)-4-(oxiranylmethoxy)indole(0.094 g, 0.494 mmol) in MeOH (6 mL) was heated at reflux for 12 h andthen cooled and evaporated. The residue was purified using silica gelchromatography [1.4% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free baseof the title compound as a white foam (0.093 g, 43%). The oxalate saltwas prepared with 1 equiv. of oxalic acid in EtOAc. Ion Spray MS 439(M+H)⁺; 437 (M−H)⁻. [α]_(D)=0 (c 0.41, MeOH). C₂₅H₂₇FN₂O₂S.C₂H₂O₄

analysis: calculated found C 61.35 61.44 H 5.53 5.80 N 5.30 5.32

EXAMPLE 59 Preparation of(2S)-(+)-3-[(2R,4S)-4-(4-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(4-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.123 g,0.494 mmol, prepared in example 56) and (S)-4-(oxiranylmethoxy)indole(0.094 g, 0.494 mmol) in MeOH (6 mL) was heated at reflux for 12 h andthen cooled and evaporated. The residue was purified using silica gelchromatography [1.4% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free baseof the title compound as a white foam (0.069 g, 32%). The oxalate saltwas prepared with 1 equiv. of oxalic acid in EtOAc. mp (oxalate)127–130° C. Ion Spray MS 439 (M+H)⁺; 437 (M−H)⁻. [α]_(D)=12.93 (c 0.46,MeOH). C₂₅H₂₇FN₂O₂S

analysis: calculated found C 68.47 68.73 H 6.21 6.40 N 6.39 6.46

EXAMPLE 60 Preparation of(2S)-3-[(2R,4R)-4-(4-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(4-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200 g,0.802 mmol, prepared in example 56) and(2S)-4-glycidyloxy-2-methylindole (0.163 g, 0.802 mmol) in MeOH (10 mL)was heated at reflux for 16 h and then cooled and evaporated. Theresidue was purified using silica gel chromatography [1% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the title compound as a whitefoam (0.155 g, 43%). The oxalate salt was prepared with 1 equiv. ofoxalic acid in EtOAc. IR (CHCl₃) 3474, 1245 cm⁻¹. Ion Spray MS 453(M+H)⁺; 451 (M−H)⁻. [α]_(D)=0 (c 0.52, MeOH). C₂₆H₂₉FN₂O₂S

analysis: calculated found C 69.00 69.29 H 6.46 6.26 N 6.19 6.28

EXAMPLE 61 Preparation of(2S)-(+)-3-[(2S,4S)-4-(4-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(4-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200 g,0.802 mmol) and (2S)-4-glycidyloxy-2-methylindole (0.163 g, 0.802 mmol)in MeOH (10 mL) was heated at reflux for 16 h and then cooled andevaporated. The residue was purified using silica gel chromatography [1%(2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base of the title compoundas a white foam (0.131 g, 36%). The oxalate salt was prepared with 1equiv. of oxalic acid in EtOAc. IR (CHCl₃) 3474, 1243 cm⁻¹. Ion Spray MS453 (M+H)⁺; 451 (M−H)⁻. [α]_(D)=31.37 (c 0.51, MeOH). C₂₆H₂₉FN₂O₂S

analysis: calculated found C 69.00 69.23 H 6.46 6.16 N 6.19 6.20

EXAMPLE 62 Preparation of(2S)-(+)-3-[4-(4,6-Dimethylbenzo[b]thiophen-2-yl)piperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Preparation of 3,5-Dimethylbenzenethioacetaldehyde diethyl acetal.

The title compound was prepared in 95% crude yield from3,5-dimethylbenzenethiol in a manner analogous to the proceduredescribed by Graham, S. L., et. al. J. Med. Chem. 1989,32, 2548–2554.

Preparation of 4,6-Dimethylbenzo[b]thiophene.

To a biphasic mixture of polyphosphoric acid (PPA; 21.6 g) and 200 mL ofdry chlorobenzene heated to reflux was added dropwise3,5-dimethylbenzenethioacetaldehyde diethyl acetal (10.0 g, 39.3 mmol)in 30 mL of chlorobenzene over a period of 1 h. The dark green biphasicmixture was heated at reflux for an additional h. The reaction mixturewas cooled to room temperature and the organic layer was decanted offthe PPA layer. The PPA layer was cooled to 0° C. and diluted with 150 mLof H₂O. This aqueous layer was extracted with Et₂O (3×500 mL). Thecombined organic layers were dried over MgSO₄ and concentrated underreduced pressure. The residue was purified by medium pressurechromatography to give the intermediate title compound as a yellow oil(4.69 g, 74%). FDMS m/e=162 (M⁺).

Preparation of4-(4,6-Dimethylbenzo[b]thiophen-2-yl)-1,2,5,6-tetrahydropyridine.

Scheme IA, Steps A and B: To a solution of4,6-dimethylbenzo[b]-thiophene (0.750 g, 4.62 mmol) in dry THF (25 mL)at −78° C. was added 1.6 M n-BuLi in hexanes (3.18 mL, 5.08 mmol). Thesolution was stirred at −78° C. for 1 h. N-t-butoxycarbonyl-4-piperidone(0.921 g, 4.62 mmol) dissolved in THF (5 mL) was added via a cannula at−78° C. The reaction mixture was allowed to warm slowly to roomtemperature over 19 h. The reaction was quenched with saturated aqueousNH₄Cl solution (55 mL). The mixture was then extracted (3×125 mL) withEtOAc. The combined organic layers were dried over MgSO₄ and filtered.The filtrate was concentrated to give a crude tertiary alcoholintermediate (1.66 g). To a solution of the crude tertiary alcoholintermediate (1.66 g, 4.59 mmol) in dry CH₂Cl₂ (16 mL) at 0° C. wasadded 7 mL of trifluoroacetic acid. The resulting purple solution wasstirred at 0° C. for 1 h 15 min. The reaction was then quenched at 0° C.with saturated aqueous NaHCO₃ solution (80 mL). The mixture wasextracted (2×150 mL) with CH₂Cl₂. The combined organic layers were driedover MgSO₄, concentrated, and the residue was purified by silica gelchromatography (4% (10% conc. NH₄OH in MeOH)/CH₂Cl₂] to give theintermediate title compound as an orange solid (0.440 g, 39%). IR(CHCl₃) 3428 (br) cm⁻¹. Ion Spray MS 244 (M+H)⁺; 215 (M−28)⁺ (basepeak).

Preparation of 4-(4,6-Dimethylbenzo[b]thiophen-2-yl)piperidine.

Scheme IA, Step C: To a solution of4-(4,6-dimethylbenzo[b]thiophen-2-yl)-1,2,5,6-tetrahydropyridine (0.435g, 1.79 mmol) in a 3:1 mixture of ethanol (13.5 mL) and2,2,2-trifluoroethanol (4.5 mL) was added 10% Pd/C (0.450 g). The blackslurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 22 h. The black slurry was then filtered over apad of diatomaceous earth and washed with ethanol. The filtrate was thenconcentrated, and the residue was purified by silica gel chromatography(5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the intermediate title compoundas an off-white solid (0.253 g, 58%). mp 83–88° C. Ion Spray MS 246(M+H)⁺; 290 (M+Cl)⁻.

Preparation of Final Title Compound.

Scheme IV, Step B: A solution of4-(4,6-dimethylbenzo[b]thiophen-2-yl)piperidine (0.100 g, 0.408 mmol)and (2S)-4-glycidyloxy-2-methylindole (0.083 g, 0.408 mmol) in MeOH (5mL) was heated at reflux for 10 h and then cooled and evaporated. Theresidue was purified using silica gel chromatography [1.5% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the final title compound as awhite foam (0.138 g, 75%). The oxalate salt was prepared with 1 equiv.of oxalic acid in EtOAc. mp (oxalate) 110–113° C. (dec.). IR (CHCl₃)3474, 3350 (br) cm⁻¹. Ion Spray MS 449 (M+H)⁺; 447 (M−H)⁻; 507(M+CH₃COO⁻)⁻. [α]_(D)=9.83 (c 0.41, MeOH). C₂₇H₂₇NO₄S

analysis: calculated found C 72.29 72.06 H 7.19 6.91 N 6.24 6.35

EXAMPLE 63 Preparation of(2S)-(−)-3-[(2R,4R)-4-(4,6-Dimethylbenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Preparation ofN-t-Butoxycarbonyl-4-(4,6-dimethylbenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol.

Scheme IA, Step A: To a solution of 4,6-dimethylbenzo[b]thiophene (3.71g, 22.9 mmol) in dry THF (115 mL) at −78° C. was added 1.6 M n-BuLi inhexanes (15.7 mL, 25.2 mmol). The solution was stirred at −78° C. for 1h. N-t-butoxycarbonyl-2-methyl-4-piperidone (4.39 g, 20.6 mmol)dissolved in THF (10 mL) was added via a cannula at −78° C. The reactionmixture was allowed to warm to room temperature over 19 h. The reactionwas then quenched with 240 mL of saturated aqueous NH₄Cl solution. Themixture was extracted (3×500 mL) with EtOAc. The combined organic layerswere dried over MgSO₄ and filtered. The filtrate was concentrated andpurified by medium pressure chromatography (silica gel, 10%EtOAc/hexanes) to give the intermediate title compound as a yellow foam(4.11 g, 37%). IR (CHCl₃) 3550 (br), 1680 cm⁻¹. Ion Spray MS 376 (M+H)⁺;302 (M−74)⁺ (base peak); 434 (M+CH₃COO⁻)⁻. ¹HNMR (CDCl₃) 7.42 (s, 1H),7.14 (s, 1H), 6.94 (s, 1H), 4.45 (br m, 1H), 4.03–4.09 (br m, 1H), 3.35(br t, 1H), 2.51 (s, 3H), 2.39 (s, 3H), 2.19 (dd, J=14.7, 6.8 Hz, 1H),1.92–2.09 (m, 3H), 1.59 (s, 1H), 1.47 (s, 9H), 1.39 (d, J=7.3 Hz, 3H).

Preparation of(±)-cis-4-(4,6-Dimethylbenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-(4,6-dimethylbenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(4.11 g, 10.9 mmol) in dry CH₂Cl₂ (38 mL) at 0° C. was added 17 mL oftrifluoroacetic acid. The resulting purple solution was stirred at 0° C.for 1 h 15 min. The reaction was then quenched at room temperature withsaturated aqueous NaHCO₃ solution (180 mL). The mixture was extracted(2×300 mL) with CH₂Cl₂. The combined organic layers were dried overMgSO₄ and concentrated to yield 3.43 g of crude regioisomeric olefins.To a solution of the crude olefins (3.43 g) in a 3:1 mixture of ethanol(100 mL) and 2,2,2-trifluoroethanol (33 mL) was added 10% Pd/C (3.25 g).The black slurry was stirred vigorously at room temperature underhydrogen (balloon pressure) for 16 h. The black slurry was then filteredover a pad of diatomaceous earth and washed with ethanol. The filtratewas concentrated, and the residue was purified by medium pressurechromatography (silica gel, 4–5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give theintermediate title compound as an orange oil (1.44 g, 51%). mp 52–57° C.Ion Spray MS 260 (M+H)⁺.

Preparation of(±)-trans-4-(4,6-Dimethylbenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-(4,6-dimethylbenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(4.11 g, 10.9 mmol) in dry

CH₂Cl₂ (38 mL) at 0° C. was added 17 mL of trifluoroacetic acid. Theresulting purple solution was stirred at 0° C. for 1 h 15 min. Thereaction was then quenched at room temperature with saturated aqueousNaHCO₃ solution (180 mL). The mixture was extracted (2×300 mL) withCH₂Cl₂. The combined organic layers were dried over MgSO₄ andconcentrated to yield 3.43 g of crude regioisomeric olefins. To asolution of the crude olefins (3.43 g) in a 3:1 mixture of ethanol (100mL) and 2,2,2-trifluoroethanol (33 mL) was added 10% Pd/C (3.25 g). Theblack slurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 16 h. The black slurry was then filtered over apad of diatomaceous earth and washed with ethanol. The filtrate wasconcentrated, and the residue was purified by medium pressurechromatography (silica gel, 4–5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give theintermediate title compound as an orange oil (0.490 g, 17%). mp 59–64°C. Ion Spray MS 260 (M+H)⁺.

Preparation of Final Title Compound.

Scheme IV, Step B: A solution of(±)-cis-4-(4,6-dimethylbenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200g, 0.771 mmol) and (2S)-4-glycidyloxy-2-methylindole (0.157 g, 0.771mmol) in MeOH (10 mL) was heated at reflux for 16 h and then cooled andevaporated. The residue was purified using silica gel chromatography [1%(2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base of the title compoundas an off-white foam (0.146 g, 41%). The oxalate salt was prepared with1 equiv. of oxalic acid in EtOAc. mp (oxalate) 109–112° C. (dec.). IR(CHCl₃) 3474, 3350 (br) cm¹. Ion Spray MS 463 (M+H)⁺, 461 (M−H)⁻.[α]_(D)=−7.09 (c 0.56, MeOH). C₂₈H₃₄N₂O₂S.0.1 CH₂Cl₂

analysis: calculated found C 71.63 71.86 H 7.32 7.26 N 5.95 6.07

EXAMPLE 64 Preparation of(2S)-(+)-3-[(2S,4S)-4-(4,6-Dimethylbenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(4,6-dimethylbenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200g, 0.771 mmol, prepared in example 63) and(2S)-4-glycidyloxy-2-methylindole (0.157 g, 0.771 mmol) in MeOH (10 mL)was heated at reflux for 16 h and then cooled and evaporated. Theresidue was purified using silica gel chromatography [1% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the title compound as anoff-white foam (0.079 g, 22%). The oxalate salt was prepared with 1equiv. of oxalic acid in EtOAc. IR (CHCl₃) 3474, 3350 (br) cm⁻¹. IonSpray MS 463 (M+H)⁺; 461 (M−H)⁺. [α]_(D)=25.21 (c 0.56, MeOH).C₂₆H₃₀N₂O₃S.C₂H₂O₄

analysis: calculated found C 65.20 65.25 H 6.57 6.62 N 5.07 5.05

EXAMPLE 65 Preparation of(2S)-3-[(2S,4R)-4-(4,6-Dimethylbenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(4,6-dimethylbenzo[b]thiophen-2-yl)-2-methylpiperidine(0.200 g, 0.771 mmol, prepared in example 63) and(2S)-4-glycidyloxy-2-methylindole (0.157 g, 0.771 mmol) in MeOH (10 mL)was heated at reflux for 16 h and then cooled and evaporated. Theresidue was purified using silica gel chromatography [1% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the title propanol as an off-white foam (0.149 g,42%). The oxalate salt was prepared with 1 equiv. of oxalic acid inEtOAc. mp (oxalate) 139–142° C. (dec.). IR (CHCl₃) 3474, 3350 (br) cm⁻¹.Ion Spray MS 463 (M+H)⁺; 461 (M−H)⁻. [α]_(D)=0 (C 0.51, MeOH).C₂₈H₃₄N₂O₂S.0.2CH₂Cl₂

analysis: calculated found C 70.62 70.88 H 7.23 6.96 N 5.84 5.83

EXAMPLE 66 Preparation of(2S)-(+)-3-[(2R,4S)-4-(4,6-Dimethylbenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(4,6-dimethylbenzo[b]thiophen-2-yl)-2-methylpiperidine(0.200 g, 0.771 mmol, prepared in example 63) and(2S)-4-glycidyloxy-2-methylindole (0.157 g, 0.771 mmol) in MeOH (10 mL)was heated at reflux for 16 h and then cooled and evaporated. Theresidue was purified using silica gel chromatography [1% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the title compound as anoff-white foam (0.1401 g, 28%). The oxalate salt was prepared with 1equiv. of oxalic acid in EtOAc. mp (oxalate) 143–146° C. (dec.). IR(CHCl₃) 3474, 3350 (br) cm⁻¹. Ion Spray MS 463 (M+H)⁺; 461 (M−H)⁻.[α]_(D)=11.80 (c 0.51, MeOH). C₂₈H₃₄N₂O₂S.C₂H₂O₄

analysis: calculated found C 65.20 64.82 H 6.57 6.26 N 5.07 4.93

EXAMPLE 67 Preparation of(2S)-(−)-3-[(2R,4R)-4-(4,6-Dimethylbenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(4,6-dimethylbenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200g, 0.771 mmol, prepared in example 63) and (S)-4-(oxiranylmethoxy)indole(0.146 g, 0.771 mmol) in MeOH (10 mL) was heated at reflux for 6 h andthen cooled and evaporated. The residue was purified using silica gelchromatography [1% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a white foam (0.151 g, 44%). The oxalate salt wasprepared with 1 equiv. of oxalic acid in EtOAc. IR (CHCl₃) 3482, 3350(br) cm⁻¹. Ion Spray MS 449 (M+H)⁺; 447 (M−H)⁻. [α]_(D)=−10.05 (c 0.60,MeOH). C₂₇H₃₂N₂O₂S.1.1C₂H₂O₄.0.1C₄H₈O₂

analysis: calculated found C 63.89 63.86 H 6.34 5.95 N 5.03 4.84

EXAMPLE 68 Preparation of(2S)-(+)-3-[(2S,4S)-4-(4,6-Dimethylbenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(4,6-dimethylbenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200g, 0.771 mmol, prepared in example 63) and (S)-4-(oxiranylmethoxy)indole(0.146 g, 0.771 mmol) in MeOH (10 mL) was heated at reflux for 6 h andthen cooled and evaporated. The residue was purified using silica gelchromatography [1% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a white foam (0.156 g, 45%). The oxalate salt wasprepared with 1 equiv. of oxalic acid in EtOAc. IR (CHCl₃) 3482, 3350(br) cm⁻¹. Ion Spray MS 449 (M+H)⁺; 447 (M−H)⁻. [α]_(D)=30.17 (c 0.53,MeOH). C₂₇H₃₂N₂O₂S.0.2H₂O

analysis: calculated found C 71.71 71.52 H 7.22 7.61 N 6.19 6.09

EXAMPLE 69 Preparation of(2S)-3-[(2S,4R)-4-(4,6-Dimethylbenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(4,6-dimethylbenzo[b]thiophen-2-yl)-2-methylpiperidine(0.200 g, 0.771 mmol, prepared in example 63) and(S)-4-(oxiranylmethoxy)indole (0.146 g, 0.771 mmol) in MeOH (10 mL) washeated at reflux for 6 h and then cooled and evaporated. The residue waspurified using silica gel chromatography [1% (2.0 M NH₃ in MeOH)/CH₂Cl₂]to give the free base of the title compound as a white foam (0.149 g,43%). The oxalate salt was prepared with 1 equiv. of oxalic acid inEtOAc. mp (oxalate) 117–120° C. IR (CHCl₃) 3482, 3350 (br) cm⁻¹. IonSpray MS 449 (M+H)⁺; 447 (M−H)⁻. [α]_(D)=0 (c 0.47, MeOH). C₂₇H₃₂N₂O₂S

analysis: calculated found C 72.29 72.49 H 7.19 6.89 N 6.24 6.48

EXAMPLE 70 Preparation of(2S)-(+)-3-[(2R,4S)-4-(4,6-Dimethylbenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(4,6-dimethylbenzo[b]-thiophen-2-yl)-2-methylpiperidine(0.200 g, 0.771 mmol, prepared in example 63) and(S)-4-(oxiranylmethoxy)indole (0.146 g, 0.771 mmol) in MeOH (10 mL) washeated at reflux for 6 h and then cooled and evaporated. The residue waspurified using silica gel chromatography [1% (2.0 M NH₃ in MeOH)/CH₂Cl₂]to give the free base of the title compound as a white foam (0.092 g,27%). The oxalate salt was prepared with 1 equiv. of oxalic acid inEtOAc. mp (oxalate) 147–150° C. (dec.). IR (CHCl₃) 3482, 3350 (br) cm⁻¹.Ion Spray MS 449 (M+H)⁺; 447 (M−H)⁻. [α]_(D)=15.98 (c 0.50, MeOH).C₂₇H₃₂N₂O₂S

analysis: calculated found C 72.29 72.05 H 7.19 7.40 N 6.24 6.32

EXAMPLE 71 Preparation of(2S)-(−)-3-[(2R,4R)-4-(4,6-Dimethoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Preparation ofN,N-Dimethyl-2-(2,4-dimethoxyphenyl)-2-hydroxythioacetamide.

To a solution of lithium diisopropylamide (108 mmol) in 400 mL of dryTHF cooled to −78° C. was added 2,4-dimethoxybenzaldehyde (15.00 g, 90.3mmol) and N,N-dimethylthioformamide (7.69 mL, 90.3 mmol) dissolved in 55mL of dry THF via a cannula over a period of 10 min. The reactionmixture was stirred at −78° C. for 30 min then warmed to 0° C. andquenched with saturated aqueous NH₄Cl solution (450 mL). The mixture wasextracted with (3×1 L) EtOAc. The combined organic layers were driedover MgSO₄ and concentrated. The residue was then recrystallized fromEtOAc/hexanes to give the intermediate title compound as a tan solid(12.9 g, 50%). IR (CHCl₃) 3250 (br) cm⁻¹. FDMS m/e=255 (M⁺). ¹HNMR(CDCl₃) 7.24 (d, J=8.3 Hz, 1H), 6.43 (d, J=2.2 Hz, 1H), 6.41 (dd, J=8.3,2.2 Hz, 1H), 5.70 (s, 1H), 3.86 (s, 3H), 3.77 (s, 3H), 3.47 (s, 3H),3.02 (s, 3H).

Preparation of 4,6-Dimethoxy-2-dimethylaminobenzo[b]thiophene.

N,N-Dimethyl-2-(2,4-dimethoxyphenyl)-2-hydroxythioacetamide (12.0 g,47.0 mmol) was dissolved in Eaton's reagent (7.5% w/w P₂O₅/MeSO₃H) (80mL). The reaction mixture was heated to 80° C. and stirred for 1 h 20min. The reaction was quenched by pouring the reaction mixture slowlyinto cooled (0° C.) 5.0 N NaOH (280 mL). The mixture was extracted(3×750 mL) with EtOAc. The combined organic layers were then dried overMgSO₄, concentrated, and the residue was purified by medium pressurechromatography (silica gel, 8% Et₂O/hexanes) to give the intermediatetitle compound as a light yellow oil (2.34 g, 21%). IR (CHCl₃) 1369, 958cm⁻¹. Ion Spray MS 238 (M+H)⁺ (base peak); 223 (M−CH₂)⁺; 207 (M−2CH₂)⁺.¹HNMR (CDCl3) 6.73 (d, J=2.0 Hz, 1H), 6.35 (d, J=2.0 Hz, 1H), 6.05 (brs, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 2.94 (s, 6H).

Preparation of 4,6-Dimethoxythianapthen-2-one.

4,6-Dimethoxy-2-dimethylaminobenzo[b]thiophene (2.32 g, 9.76 mmol) wasdissolved in a 1:1 mixture of THF/1.0 N HCl (70 mL). The biphasicmixture was stirred vigorously and heated at reflux for 2 h. Thereaction mixture was then cooled to room temperature and the layers wereseparated. The aqueous layer was extracted (2×125 mL) with EtOAc. Thecombined organic layers were dried over MgSO₄ and concentrated to givethe intermediate title compound as a white solid (2.05 g, quantitativeyield). mp 135–137° C. IR (CHCl₃) 1716 cm⁻¹. Ion Spray MS 211 (M+H)⁺;183 (M−27)⁺ (base peak).

Preparation of 4,6-Dimethoxybenzo[b]thiophene.

To a solution of 4,6-dimethoxythianapthen-2-one (2.01 g, 9.57 mmol) inCH₂Cl₂ (100 mL) was added dropwise 1.0 M diisobutylaluminum hydride intoluene (10.5 mL, 10.5 mmol) at 0° C. The solution was stirred at 0° C.for 15 min. The reaction was quenched with conc. HCl (60 mL). Thismixture was then stirred vigorously for 1 h. The layers were separated,and the organic layer was dried over MgSO₄ and concentrated. The residuewas purified by medium pressure chromatography (100% hexanes) to givethe intermediate title compound as a white solid (1.10 g, 59%). mp78–80° C. IR (CHCl₃) 1149, 1046 cm⁻¹. Ion Spray MS 195 (M+H)⁺.

Preparation ofN-t-Butoxycarbonyl-4-(4,6-dimethoxybenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol.

Scheme IA, Step A: To a solution of 4,6-dimethoxybenzo[b]thiophene (1.07g, 5.52 mmol) in dry THF (30 mL) at −78° C. was added 1.6 M n-BuLi inhexanes (3.80 mL, 6.07 mmol). The solution was stirred at −78° C. for 45min. N-t-butoxycarbonyl-2-methyl-4-piperidone (1.18 g, 5.52 mmol)dissolved in THF (7 mL) was added via a cannula at −78° C. The reactionmixture was allowed to warm to room temperature over 16 h. The reactionwas then quenched with 65 mL of saturated aqueous NH₄Cl solution. Themixture was extracted (2×100 mL) with EtOAc. The combined organic layerswere then dried over MgSO₄ and filtered. The filtrate was concentratedand purified by silica gel chromatography (20% EtOAc/hexanes) to givethe intermediate title compound as a yellow foam (0.590 g, 26%). IR(CHCl₃) 3474, 3350 (br) cm⁻¹. IR (CHCl₃) 3350 (br), 1680 cm⁻¹. Ion SprayMS 408 (M+H)⁺; 390 (M−H₂0)⁺; 334 (M−74)⁺ (base peak); 466(M+CH₃COO⁻)⁻.¹HNMR (CDCl₃) 7.17 (s, 1H), 6.83 (d, J=2.0 Hz, 1H), 6.36 (d, J=2.0 Hz,1H), 4.43 (br m, 1H), 3.97–4.00 (br m, 1H), 3.87 (s, 3H), 3.82 (s, 3H),3.33 (br t, 1H), 2.15 (dd, J=14.7, 6.8 Hz, 1H), 1.89–2.05 (m, 3H), 1.47(s, 1H), 1.46 (s, 9H), 1.37 (d, J=7.3 Hz, 3H).

Preparation of(±)-cis-4-(4,6-Dimethoxybenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-(4,6-dimethoxybenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(1.23 g, 3.03 mmol) in dry CH₂Cl₂ (10.5 mL) at 0° C. was added 4.5 mL oftrifluoroacetic acid. The solution was stirred at 0° C. for 1 h 30 min.The reaction was then quenched at room temperature with saturatedaqueous NaHCO₃ solution (60 mL). The mixture was extracted (2×125 mL)with CH₂Cl₂. The combined organic layers were dried over MgSO₄ andconcentrated to yield 1.02 g of crude regioisomeric olefins. To asolution of the crude olefins (1.02 g) in a 3:1 mixture of ethanol (23mL) and 2,2,2-trifluoroethanol (8 mL) was added 10% Pd/C (1.10 g). Theblack slurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 2.5 days. The black slurry was then filtered overa pad of diatomaceous earth and washed with ethanol. The filtrate wasconcentrated, and the residue was purified by silica gel chromatography(4–5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the intermediate titlecompound as a yellow semi-solid (0.276 g, 31%). Ion Spray MS 292 (M+H)⁺.

Preparation of(±)-trans-4-(4,6-Dimethoxybenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-(4,6-dimethoxybenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(1.23 g, 3.03 mmol) in dry CH₂Cl₂ (10.5 mL) at 0° C. was added 4.5 mL oftrifluoroacetic acid. The solution was stirred at 0° C. for 1 h 30 min.The reaction was then quenched at room temperature with saturatedaqueous NaHCO₃ solution (60 mL). The mixture was extracted (2×125 mL)with CH₂Cl₂. The combined organic layers were dried over MgSO₄ andconcentrated to yield 1.02 g of crude regioisomeric olefins. To asolution of the crude olefins (1.02 g) in a 3:1 mixture of ethanol (23mL) and 2,2,2-trifluoroethanol (8 mL) was added 10% Pd/C (1.10 g). Theblack slurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 2.5 days. The black slurry was then filtered overa pad of diatomaceous earth and washed with ethanol. The filtrate wasconcentrated, and the residue was purified by silica gel chromatography(4–5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the intermediate titlecompound as a yellow semi-solid (0.102 g, 12%). Ion Spray MS 292 (M+H)⁺.

Preparation of Final Title Compound.

Scheme IV, Step B: A solution of(±)-cis-4-(4,6-dimethoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.203g, 0.697 mmol) and (2S)-4-glycidyloxy-2-methylindole (0.142 g, 0.697mmol) in MeOH (10 mL) was heated at reflux for 18 h and then cooled andevaporated. The residue was purified using silica gel chromatography[1.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base of the finaltitle compound as a white foam (0.117 g, 34%). The oxalate salt wasprepared with 1 equiv. of oxalic acid in EtOAc. mp (oxalate) 117–121° C.(dec.). IR (CHCl₃) 3474, 3350 (br) cm⁻¹. Ion Spray MS 495 (M+H)⁺; 493(M−H)⁻. [α]_(D)=−3.51 (c 0.57, MeOH). C₂₈H₃₄N₂O₄S.0.1CH₂Cl₂

analysis: calculated found C 67.08 66.73 H 6.85 6.84 N 5.57 5.48

EXAMPLE 72 Preparation of (2S)-(+)-3-[(2S,4S)-4-(4,6-Dimethoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(4,6-dimethoxybenzo[b]-thiophen-2-yl)-2-methylpiperidine(0.203 g, 0.697 mmol, prepared in example 71) and(2S)-4-glycidyloxy-2-methylindole (0.142 g, 0.697 mmol) in MeOH (10 mL)was heated at reflux for 18 h and then cooled and evaporated. Theresidue was purified using silica gel chromatography [1.5% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the final title compound as awhite foam (0.127 g, 37%). The oxalate salt was prepared with 1 equiv.of oxalic acid in EtOAc. mp (oxalate) 142–145° C. (dec.). IR (CHCl₃)3474, 3350 (br) cm⁻¹. Ion Spray MS 495 (M+H)⁺; 493 (M−H)⁻. [α]_(D)=21.99(c 0.45, MeOH). C₂₈H₃₄N₂O₄S

analysis: calculated found C 67.99 67.99 H 6.93 7.17 N 5.66 5.57

EXAMPLE 73 Preparation of (2S,)-3-[(2S4R)-4-(4,6-Dimethoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(4,6-dimethoxybenzo[b]thiophen-2-yl)-2-methylpiperidine(0.091 g, 0.313 mmol, prepared in example 71) and(2S)-4-glycidyloxy-2-methylindole (0.064 g, 0.313 mmol) in MeOH (5 mL)was heated at reflux for 24 h and then cooled and evaporated. Theresidue was purified using silica gel chromatography [1.5% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the title compound as a whitefoam (0.056 g, 36%). The oxalate salt was prepared with 1 equiv. ofoxalic acid in EtOAc. Ion Spray MS 495 (M+H)⁺; 493 (M−H)⁻.C₂₈H₃₄N₂O₄S.0.2CH₂Cl₂

analysis: calculated found C 66.20 66.28 H 6.78 6.83 N 5.48 5.60

EXAMPLE 74 Preparation of(2S)-(+)-3-[(2R,4S)-4-(4,6-Dimethoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(4,6-dimethoxybenzo[b]thiophen-2-yl)-2-methylpiperidine(0.091 g, 0.313 mmol, prepared in example 71) and(2S)-4-glycidyloxy-2-methylindole (0.064 g, 0.313 mmol) in MeOH (5 mL)was heated at reflux for 24 h and then cooled and evaporated. Theresidue was purified using silica gel chromatography [1.5% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the title compound as a whitefoam (0.077 g, 49%). The oxalate salt was prepared with 1 equiv. ofoxalic acid in EtOAc. IR (CHCl₃) 3474, 3350 (br) cm⁻¹. Ion Spray MS 495(M+H)⁺; 493 (M−H)⁻. [α]_(D)=11.01 (c 0.36, MeOH). C₂₈H₃₄N₂O₄S.0.2CH₂Cl₂

analysis: calculated found C 66.20 66.25 H 6.78 6.88 N 5.48 5.48

EXAMPLE 75 Preparation of(2S)-3-[4-(5-Fluorobenzo[b]thiophen-2-yl)piperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Preparation of 4-Fluorobenzenethioacetaldehyde diethyl acetal.

The intermediate title compound was prepared in 95% crude yield from4-flourobenzenethiol in a manner analogous to the procedure described byGraham, S. L., et. al. J. Med. Chem. 1989,32, 2548–2554.

Preparation of 5-Fluorobenzo[b]thiophene.

A slurry of amberlyst-15 (19.0 g) in 1,1,2-trichloroethane (285 mL) washeated at reflux. Approximately 30 mL of wet distillate was removed(cloudy in appearance) via a Dean-Stark trap.4-Fluorobenzenethioacetaldehyde diethyl acetal (19.0 g, 77.8 mmol) wasdissolved in 1,1,2-trichloroethane (95 mL) and added dropwise to theslurry at reflux over a period of 1 h 15 min. Distillate was removed atan approximate rate of 0.5 mL/min. The reaction mixture was cooled toroom temperature and filtered with CH₂Cl₂ rinse. The filtrate andwashing were concentrated, and the residue was purified by mediumpressure chromatography (silica gel, 100% hexanes) to give theintermediate title compound as a colorless oil (2.81 g, 24%). Ion SprayMS 211 (M+CH₃COO)⁻. ¹HNMR (CDCl₃) 7.78 (dd, J=8.8, 4.9 Hz, 1H), 7.51 (d,J=5.4 Hz, 1H), 7.46 (dd, J=9.3, 2.4 Hz, 1H), 7.27 (d, J=5.4 Hz, 1H),7.09 (dt, J=8.8, 2.4 Hz, 1H).

Preparation of4-(5-Fluorobenzo[b]thiophen-2-yl)-1,2,5,6-tetrahydropyridine.

Scheme IA, Steps A and B: To a solution of 5-fluorobenzo[b]thiophene(0.500 g, 3.29 mmol) in dry THF (15 mL) at −78° C. was added 1.6 Mn-BuLi in hexanes (2.26 mL, 3.61 mmol). The solution was stirred at −78°C. for 45 min. N-t-Butoxycarbonyl-4-piperidone (0.786 g, 3.94 mmol)dissolved in THF (7 mL) was added via a cannula at −78° C. The reactionmixture was allowed to warm slowly to −30° C. over 2 h. The reaction wasquenched with saturated aqueous NH₄Cl solution (50 mL). The mixture wasextracted (3×100 mL) with EtOAc. The combined organic layers were driedover MgSO₄ and filtered. The filtrate was concentrated to give a crudetertiary alcohol intermediate (1.29 g). To a solution of the crudetertiary alcohol intermediate (1.29 g, 3.67 mmol) in dry CH₂Cl₂ (11 mL)at 0° C. was added 5 mL of trifluoroacetic acid. The resulting solutionwas stirred at 0° C. for 2.5 h. The reaction was then quenched at 0° C.with saturated aqueous NaHCO₃ solution (65 mL). The mixture wasextracted (2×125 mL) with CH₂Cl₂. The combined organic layers were driedover MgSO₄ and concentrated to give the intermediate title compound asan off-white solid (0.450 g, 59%). IR (CHCl₃) 1445 cm⁻¹. Ion Spray MS234 (M+H)⁺.

Preparation of 4-(5-Fluorobenzo[b]thiophen-2-yl)piperidine.

Scheme IA, Step C: To a solution of4-(5-fluorobenzo[b]thiophen-2-yl)-1,2,5,6-tetrahydropyridine (0.440 g,1.89 mmol) in a 3:1 mixture of ethanol (15 mL) and2,2,2-trifluoroethanol (5 mL) was added 10% Pd/C (0.450 g). The blackslurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 20 h. The black slurry was then filtered over apad of diatomaceous earth and washed with ethanol. The filtrate wasconcentrated, and the residue was purified by silica gel chromatography[6% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the intermediate title compoundas a white solid (0.270 g, 61%). IR (CHCl₃) 1446 cm⁻¹. Ion Spray MS 236(M+H)⁺.

Preparation of Final Title Compound.

Scheme IV, Step B: A solution of4-(5-fluorobenzo[b]thiophen-2-yl)piperidine (0.100 g, 0.425 mmol) and(2S)-4-glycidyloxy-2-methylindole (0.086 g, 0.425 mmol) in MeOH (5 mL)was heated at reflux for 18 h and then cooled and evaporated. Theresidue was purified using silica gel chromatography [1% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the final title compound as awhite foam (0.145 g, 79%). The oxalate salt was prepared with 1 equiv.of oxalic acid in EtOAc. IR (CHCl₃) 3474, 3350 (br), 1247 cm⁻¹. IonSpray MS 439 (M+H)⁺; 437 (M−H)⁻. [α]_(D)=0 (c 0.40, MeOH). C₂₅H₂₇FN₂O₂S

analysis: calculated found C 68.47 68.64 H 6.21 6.35 N 6.39 6.39

EXAMPLE 76 Preparation of(2S)-(−)-3-[(2R,4R)-4-(5-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Preparation ofN-t-Butoxycarbonyl-4-(5-fluorobenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol.

Scheme IA, Step A: To a solution of 5-fluorobenzo[b]thiophene (2.25 g,14.8 mmol, prepared in example 75) in dry THF (65 mL) at −78° C. wasadded 1.6 M n-BuLi in hexanes (10.1 mL, 16.2 mmol). The solution wasstirred at −78° C., for 45 min. N-t-butoxycarbonyl-2-methyl-4-piperidone(3.15 g, 14.8 mmol) dissolved in THF (15 mL) was added via a cannula at−78° C. The reaction mixture was warmed slowly to −50° C. over 19 h. Thereaction was then quenched with 130 mL of saturated aqueous NH₄Clsolution. The mixture was extracted (2×300 mL) with EtOAc. The combinedorganic layers were dried over MgSO₄ and filtered. The filtrate wasconcentrated and purified by medium pressure chromatography (silica gel,25–30% EtOAc/hexanes) to give the intermediate title compound as a whitesolid (2.64 g, 49%). IR (CHCl₃) 1680, 1418,1161 cm⁻¹. Ion Spray MS 366(M+H)⁺; 424 (M+CH₃COO⁻)⁻.

Preparation of(±)-cis-4-(5-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-(5-fluorobenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(2.63 g, 7.19 mmol) in dry CH₂Cl₂ (22 mL) at 0° C. was added 10 mL oftrifluoroacetic acid. The solution was stirred at 0° C. for 1 h 30 min.The reaction was then quenched at room temperature with saturatedaqueous NaHCO₃ solution (130 mL). The mixture was extracted (2×250 mL)with CH₂Cl₂. The combined organic layers were dried over MgSO₄ andconcentrated to yield 1.82 g of crude regioisomeric olefins. To asolution of the crude olefins (1.82 g) in a 3:1 mixture of ethanol (54mL) and 2,2,2-trifluoroethanol (18 mL) was added 10% Pd/C (1.85 g). Theblack slurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 16 h. The black slurry was then filtered over apad of diatomaceous earth and washed with ethanol. The filtrate was thenconcentrated, and the residue was purified by silica gel chromatography[5.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to the intermediate title compound asa white solid (0.692 g, 39%). IR (CHCl₃) 1446 cm⁻¹. Ion Spray MS 250(M+H)⁺.

Preparation of(±)-trans4-(5-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-(5-fluorobenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(2.63 g, 7.19 mmol) in dry CH₂Cl₂ (22 mL) at 0° C. was added 10 mL oftrifluoroacetic acid. The solution was stirred at 0° C. for 1 h 30 min.The reaction was then quenched at room temperature with saturatedaqueous NaHCO₃solution (130 mL). The mixture was extracted (2×250 mL)with CH₂Cl₂. The combined organic layers were dried over MgSO₄ andconcentrated to yield 1.82 g of crude regioisomeric olefins. To asolution of the crude olefins (1.82 g) in a 3:1 mixture of ethanol (54mL) and 2,2,2-trifluoroethanol (18 mL) was added 10% Pd/C (1.85 g). Theblack slurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 16 h. The black slurry was then filtered over apad of diatomaceous earth and washed with ethanol. The filtrate was thenconcentrated, and the residue was purified by silica gel chromatography[5.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the intermediate titlecompound as a white solid (0.438 g, 24%). IR (CHCl₃) 1445 cm⁻¹. IonSpray MS 250 (M+H)⁺.

Preparation of Final Title Compound.

Scheme IV, Step B: A solution of(±)-cis-4-(5-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200 g,0.802 mmol) and (2S)-4-glycidyloxy-2-methylindole (0.163 g, 0.802 mmol)in MeOH (10 mL) was heated at reflux for 20 h and then cooled andevaporated. The residue was purified using silica gel chromatography[1–1.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base of the finaltitle compound as a white foam (0.156 g, 43%). The oxalate salt wasprepared with 1 equiv. of oxalic acid in EtOAc. IR (CHCl₃) 3474, 3350(br), 1246 cm⁻¹. Ion Spray MS 453 (M+H)⁺; 451 (M−H)⁻. [α]_(D)=−8.61 (c0.47, MeOH). C₂₆H₂₉FN₂O₂S

analysis: calculated found C 69.00 69.30 H 6.46 6.53 N 6.19 6.25

EXAMPLE 77 Preparation of(2S)-(+)-3-[(2S,4S)-4-(5-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(5-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200 g,0.802 mmol, prepared in example 76) and(2S)-4-glycidyloxy-2-methylindole (0.163 g, 0.802 mmol) in MeOH (10 mL)was heated at reflux for 20 h and then cooled and evaporated. Theresidue was purified using silica gel chromatography [1–1.5% (2.0 M NH₃in MeOH)/CH₂Cl₂] to give the free base of the title compound as a whitefoam (0.165 g, 45%). The oxalate salt was prepared with 1 equiv. ofoxalic acid in EtOAc. IR (CHCl₃) 3474, 3350 (br), 1246 cm⁻¹. Ion SprayMS 453 (M+H)⁺; 451 (M−H)⁻. [α]_(D)=30.27 (c 0.46, MeOH). C₂₆H₂₉FN₂O₂S

analysis: calculated found C 69.00 69.27 H 6.46 6.70 N 6.19 6.35

EXAMPLE 78 Preparation of(2S)-3-[(2S,4R)-4-(5-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(5-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200 g,0.802 mmol, prepared in example 76) and(2S)-4-glycidyloxy-2-methylindole (0.163 g, 0.802 mmol) in MeOH (10 mL)was heated at reflux for 22 h and then cooled and evaporated. Theresidue was purified using silica gel chromatography [1–1.5% (2.0 M NH₃in MeOH)/CH₂Cl₂] to give the free base of the title compound as a whitefoam (0.159 g, 44%). The oxalate salt was prepared with 1 equiv. ofoxalic acid in EtOAc. IR (CHCl₃) 3474, 3350 (br), 1246 cm⁻¹. Ion SprayMS 453 (M+H)⁺; 451 (M−H)⁻. [α]_(D)=0 (c 0.42, MeOH). C₂₆H₂₉FN₂O₂S

analysis: calculated found C 69.00 69.30 H 6.46 6.51 N 6.19 6.42

EXAMPLE 79 Preparation of(2S)-(+)-3-[(2R,4S)-4-(5-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol

Scheme IV, Step B: A solution of(±)-trans-4-(5-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200 g,0.802 mmol, prepared in example 76) and(2S)-4-glycidyloxy-2-methylindole (0.163 g, 0.802 mmol) in MeOH (10 mL)was heated at reflux for 22 h and then cooled and evaporated. Theresidue was purified using silica gel chromatography [1–1.5% (2.0 M NH₃in MeOH)/CH₂Cl₂] to give the free base of the title compound as a whitefoam (0.163 g, 45%). The oxalate salt was prepared with 1 equiv. ofoxalic acid in EtOAc. IR (CHCl₃) 3474, 3350 (br), 1246 cm⁻¹. Ion SprayMS 453 (M+H)⁺; 451 (M−H)⁻. [α]_(D)=13.84 (c 0.58, MeOH).C₂₅H₂₇FN₂O₂S.0.2H₂O

analysis: calculated found C 68.45 68.45 H 6.50 6.88 N 6.14 6.12

EXAMPLE 80 Preparation of(2S)-(−)-3-[(2R,4R)-4-(5-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(5-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200 g,0.802 mmol, prepared in example 76) and (S)-4-(oxiranylmethoxy)indole(0.152 g, 0.802 mmol) in MeOH (10 mL) was heated at reflux for 24 h andthen cooled and evaporated. The residue was purified using silica gelchromatography [1–1.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free baseof the title compound as a white foam (0.123 g, 35%). The oxalate saltwas prepared with 1 equiv. of oxalic acid in EtOAc. IR (CHCl₃) 3482,3350 (br), 1244 cm⁻¹. Ion Spray MS 439 (M+H)⁺; 437 (M−H)⁻.[α]_(D)=−19.35 (c 0.31, MeOH). C₂₅H₂₇FN₂O₂S.C₂H₂O₄

analysis: calculated found C 61.35 61.06 H 5.53 5.46 N 5.30 5.35

EXAMPLE 81 Preparation of(2S)-(+)-3-[(2S,4S)-4-(5-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(5-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200 g,0.802 mmol, prepared in example 76) and (S)-4-(oxiranylmethoxy)indole(0.152 g, 0.802 mmol) in MeOH (10 mL) was heated at reflux for 24 h andthen cooled and evaporated. The residue was purified using silica gelchromatography [1–1.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free baseof the title compound as a white foam (0.098 g, 28%). The oxalate saltwas prepared with 1 equiv. of oxalic acid in EtOAc. IR (CHCl₃) 3482,3350 (br), 1243 cm⁻¹. Ion Spray MS 439 (M+H)⁺; 437 (M−H)⁻. [α]_(D)=38.30(c 0.47, MeOH). C₂₅H₂₇FN₂O₂S.C₂H₂O₄.0.2H₂O.0.3C₄H₈O₂

analysis: calculated found C 60.63 60.30 H 5.74 5.78 N 5.01 5.18

EXAMPLE 82 Preparation of(2S)-3-[(2S,4R)-4-(5-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(5-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200 g,0.802 mmol, prepared in example 76) and (S)-4-(oxiranylmethoxy)indole(0.152 g, 0.802 mmol) in MeOH (10 mL) was heated at reflux for 16 h andthen cooled and evaporated. The residue was purified using silica gelchromatography [1–1.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free baseof the title compound as a white foam (0.118 g, 34%). The oxalate saltwas prepared with 1 equiv. of oxalic acid in EtOAc. IR (CHCl₃) 3482,3350 (br) cm⁻¹. Ion Spray MS 439 (M+H)⁺; 437 (M−H)⁻. [α]_(D) (oxalate)=0(c 0.45, DMSO). C₂₅H₂₇FN₂O₂S.C₂H₂O₄

analysis: calculated found C 61.35 61.73 H 5.53 5.52 N 5.30 5.46

EXAMPLE 83 Preparation of(2S)-(+)-3-[(2R,4S)-4-(5-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(5-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200 g,0.802 mmol, prepared in 102) and (S)-4-(oxiranylmethoxy)indole (0.152 g,0.802 mmol) in MeOH (10 mL) was heated at reflux for 16 h and thencooled and evaporated. The residue was purified using silica gelchromatography [1–1.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free baseof the title compound as a white foam (0.112 g, 32%). The oxalate saltwas prepared with 1 equiv. of oxalic acid in EtOAc. IR (CHCl₃) 3482,3350 (br) cm⁻¹. Ion Spray MS 439 (M+H)⁺; 437 (M−H)⁻. [ ]_(D)=11.32 (c0.53, MeOH). C₂₅H₂₇FN₂O₂S.0.6CH₂Cl₂

analysis: calculated found C 62.81 62.62 H 5.81 5.68 N 5.72 5.89

EXAMPLE 84 Preparation of(2S)-3-[4-(8-Methoxynaphth-2-yl)piperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Preparation of 7-Bromo-1-tetralone.

1-tetralone (27.1 mL, 200 mmol) was added dropwise to aluminum chloride(66.7 g, 500 mmol) while stirred with the aid of a mechanical stirrerover a period of 7 min. To the tarry mixture was added bromine (12.4 mL,240 mmol) over a 20 min period. The mixture was then heated to 80° C.for 5 min. The hot mixture was then poured in a bath containing ice (600g) and conc. HCl (80 mL). This mixture was extracted (2×500 mL) withCH₂Cl₂. The combined organic layers were then dried over MgSO₄,concentrated, and the residue was purified using medium pressurechromatography (silica gel, 10% tert-butyl methyl ether/heptane) to givethe intermediate title compound as an orange solid (16.50 g, 37%). IR(CHCl₃) 1685 cm⁻¹. Ion Spray MS 225 (M+H)

Preparation of 7-Bromo-1-naphthol.

HCl gas was bubbled into a solution of 7-bromo-1-tetralone (16.5 g, 73.3mmol) in 750 mL of Et₂O cooled to −7° C. for 2 min. Bromine (3.78 mL,73.3 mmol) diluted with 33 mL of a mixture of 10:1 CH₂Cl₂/Et₂O was thenadded dropwise over a period of 3 h. The reaction was quenched with H₂O(200 mL). The layers were separated, and the organic layer was driedover MgSO₄ and concentrated to yield 22.0 g (72.4 mmol) of the dibromotetralone intermediate. To the intermediate dissolved in DMF (150 mL).was added lithium chloride (6.14 g, 145 mmol), and the solution washeated at reflux for 2 h. The reaction was cooled to room temperatureand quenched with 1.0 N HCl (250 mL). The mixture was extracted with(1×150, 1×75, 1×50 mL) with Et₂O. Combined organic layers were washedwith (1×100 mL) with 10% lithium chloride solution and then stirredvigorously with decolorizing carbon (8.00 g). The slurry was filteredover a pad of diatomaceous earth and washed with Et₂O. The filtrate wasconcentrated, and the residue was partitioned between 3.0 N NaOH (40 mL)and heptane (80 mL). The layers were separated. The aqueous layer wasacidified to a pH=1 with conc. HCl in the presence of CH₂Cl₂ (80 mL).The layers were partitioned, and to the organic layer was added heptane(80 mL). The solution was then concentrated at 30° C. to a volume of 80mL. Heptane was added to increase the volume to 160 mL. This wasrepeated twice. A slurry was then formed and kept in the refrigeratorovernight. The slurry was then filtered, and the precipitate was washedwith cold heptane. The precipitate was dried in a vacuum oven at 45° C.over P₂O₅ for 2 h to give the intermediate title compound as a brownsolid (8.89 g, 55%). IR (CHCl₃) 3595, 3275 (br) cm⁻¹. Ion Spray MS 221(M−H)⁻¹.

Preparation of 7-Bromo-1-methoxynaphthalene.

A slurry of 7-bromo-1-naphthol (8.89 g, 39.9 mmol), potassium carbonate(8.26 g, 59.8 mmol), dimethyl sulfate (5.66 mL, 59.8 mmol) andtetrabutylammonium bromide (0.085 g, 0.264 mmol) in acetonitrile (160mL) was heated at reflux for 2 h 45 min. The reaction was cooled to roomtemperature, and water was added (200 mL). The mixture was thenextracted (1×100, 1×40 mL) with CH₂Cl₂. The combined organic layers werewashed (1×40 mL) with saturated aqueous NaHCO₃ solution, dried overMgSO₄, and concentrated. The residue was purified by medium pressurechromatography (100% hexanes) to give the intermediate title compound asa yellow oil (8.42 g, 89%). FDMS m/e=236 M⁺.

Preparation ofN-t-Butoxycarbonyl-4-(8-methoxynaphth-2-yl)-4-piperidinol.

Scheme I, Step A: To a solution of 7-bromo-1-methoxynaphthalene (1.50 g,6.33 mmol) in dry THF (30 mL) at −78° C. was added 1.6 M n-BuLi inhexanes (4.35 mL, 6.96 mmol). The solution was stirred at −78° C. for 15min. N-t-Butoxycarbonyl-4-piperidone (1.51 g, 7.59 mmol) dissolved inTHF (10 mL) was added via a cannula at −78° C. The reaction mixture wasstirred at −78° C. for 2.5 h. The reaction was then quenched with 30 mLof saturated aqueous NH₄Cl solution. The mixture was extracted (2×150mL) with EtOAc. The combined organic layers were then dried over MgSO₄and filtered. The filtrate was concentrated and purified by silica gelchromatography (25% EtOAc/hexanes) to give the intermediate titlecompound as a white foam (1.42 g, 63%). IR (CHCl₃) 3350 (br), 1681 cm⁻¹.Ion Spray MS 358 (M+H)⁺; 240 (M−117(−(Boc+H₂0)))⁺; 430 (M+CH₃COO⁻)⁻.¹HNMR (CDCl₃) 8.31 (d, J=2.0 Hz, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.60 (dd,J=8.8, 2.0 Hz, 1H), 7.34–7.40 (m, 2H), 6.81 (dd, J=7.1, 2.0 Hz, 1H),4.03–4.06 (br m, 2H), 3.99 (s, 3H), 3.29 (br dt, J=13.0, 2.4 Hz, 2H),2.12 (dt, J=13.0, 4.9 Hz, 2H), 1.79–1.83 (br m, 2H), 1.61 (br s, 1H),1.48 (s, 9H).

Preparation of 4-(8-Methoxynaphth-2-yl)piperidine.

Scheme I, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-(8-methoxynaphth-2-yl)-4-piperidinol (1.42 g, 3.97mmol) in dry CH₂Cl₂ (12 mL) at 0° C. was added 5 mL of trifluoroaceticacid. The solution was stirred at 0° C. for 2 h. The reaction was thenquenched at room temperature with saturated aqueous NaHCO₃ solution (70mL). The mixture was extracted (2×150 mL) with CH₂Cl₂. The combinedorganic layers were dried over MgSO₄ and concentrated to yield 0.980 gof crude regioisomeric olefins. To a solution of the crude olefins(0.980 g) in a 3:1 mixture of ethanol (30 mL) and 2,2,2-trifluoroethanol(10 mL) was added 10% Pd/C (0.250 g). The black slurry was stirredvigorously at room temperature under hydrogen (balloon pressure) for 16h. The black slurry was then filtered over a pad of diatomaceous earthand washed with ethanol. The filtrate was concentrated, and the residuewas purified by silica gel chromatography [6% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the intermediate title compound as a white solid(0.508 g, 53%). Ion Spray MS 242 (M+H)⁺.

Scheme IV, Step B: A solution of 4-(8-methoxynaphth-2-yl)piperidine(0.100 g, 0.414 mmol, prepared above) and(2S)-4-glycidyloxy-2-methylindole (0.084 g, 0.414 mmol) in MeOH ( 5 mL)was heated at reflux for 16 h and then cooled and evaporated. Theresidue was purified using silica gel chromatography [1% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the title compound as a whitefoam (0.130 g, 71%). The oxalate salt was prepared with 1 equiv. ofoxalic acid in EtOAc. IR (CHCl₃) 3474, 3350 (br) cm⁻¹. Ion Spray MS 445(M+H)⁺; 443 (M−H)⁻. [α]_(D)=0 (c 0.48, MeOH).C₂₈H₃₂N₂O₃.0.8C₂H₂O₄.0.2H₂O

analysis: calculated found C 68.58 68.53 H 6.60 6.49 N 5.33 5.33

EXAMPLE 85 Preparation of(2S)-3-[(2R,4R)-4-(8-Methoxynaphth-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Preparation ofN-t-Butoxycarbonyl-4-(8-methoxynaphth-2-yl)-2-methyl-4-piperidinol.

Scheme I, Step A: To a solution of 7-bromo-1-methoxynaphthalene (6.50 g,27.4 mmol, prepared in example 84) in dry THF (140 mL) at −78° C. wasadded 1.6 M n-BuLi in hexanes (17.1 mL, 27.4 mmol). The solution wasstirred at −78° C. for 45 min. N-t-Butoxycarbonyl-2-methyl-4-piperidone(5.85 g, 27.4 mmol) dissolved in THF (25 mL) was added via a cannula at−78° C. The reaction mixture was stirred at −78° C. for 5 h. Thereaction was then quenched with 140 mL of saturated aqueous NH₄Clsolution. The mixture was extracted (2×250 mL) with EtOAc. The combinedorganic layers were then dried over MgSO₄ and filtered. The filtrate wasconcentrated and purified by medium pressure chromatography (silica gel,25% EtOAc/hexanes) to give the intermediate title compound as a whitefoam (6.06 g, 60%). IR (CHCl₃) 3350 (br), 1680 cm⁻¹. Ion Spray MS 371(M+H)⁺; 254 (M−117(−(Boc+H₂0)))⁺ (base peak); 430 (M+CH₃COO⁻)⁻.

Preparation of (±)-cis-4-(8-Methoxynaphth-2-yl)-2-methylpiperidine.

Scheme I, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-(8-methoxynaphth-2-yl)-2-methyl-4-piperidinol (6.06g, 16.3 mmol) in dry CH₂Cl₂ (49 mL) at 0° C. was added 21 mL oftrifluoroacetic acid. The solution was stirred at 0° C. for 1.5 h. Thereaction was then quenched at room temperature with saturated aqueousNaHCO₃ solution (280 mL). The mixture was extracted (2×300 mL) withCH₂Cl₂. The combined organic layers were dried over MgSO₄ andconcentrated to yield 4.02 g of crude regioisomeric olefins. To asolution of the crude olefins (4.02 g) in a 3:1 mixture of ethanol (120mL) and 2,2,2-trifluoroethanol (40 mL) was added 10% Pd/C (1.50 g). Theblack slurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 16 h. The black slurry was then filtered over apad of diatomaceous earth and washed with ethanol. The filtrate wasconcentrated, and the residue was purified by medium pressurechromatography [silica gel, 4–6% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to givecis-(±)-4-(8-methoxynaphth-2-yl)-2-methylpiperidine as a brown oil (1.86g, 45%). Ion Spray MS 256 (M+H)⁺.

Preparation of (±)-trans-4-(8-Methoxynaphth-2-yl)-2-methylpiperidine.

Scheme I, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-(8-methoxynaphth-2-yl)-2-methyl-4-piperidinol (6.06g, 16.3 mmol) in dry CH₂Cl₂ (49 mL) at 0° C. was added 21 mL oftrifluoroacetic acid. The solution was stirred at 0° C. for 1.5 h. Thereaction was then quenched at room temperature with saturated aqueousNaHCO₃ solution (280 mL). The mixture was extracted (2×300 mL) withCH₂Cl₂. The combined organic layers were dried over MgSO₄ andconcentrated to yield 4.02 g of crude regioisomeric olefins. To asolution of the crude olefins (4.02 g) in a 3:1 mixture of ethanol (120mL) and 2,2,2-trifluoroethanol (40 mL) was added 10% Pd/C (1.50 g). Theblack slurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 16 h. The black slurry was then filtered over apad of diatomaceous earth and washed with ethanol. The filtrate wasconcentrated, and the residue was purified by medium pressurechromatography [silica gel, 4–6% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give theintermediate title compound as a brown solid (0.984 g, 24%). Ion SprayMS 256 (M+H)⁺.

Preparation of Final Title Compound.

Scheme IV, Step B: A solution of(±)-cis-4-(8-methoxynaphth-2-yl)-2-methylpiperidine (1.30 g, 5.09 mmol)and (2S)-4-glycidyloxy-2-methylindole (1.030 g, 5.09 mmol) in MeOH (65mL) was heated at reflux for 20 h and then cooled and evaporated. Theresidue was purified using silica gel chromatography [1.5% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the final title compound as anoff-white foam (0.829 g, 36%). The oxalate salt was prepared with 1equiv. of oxalic acid in EtOAc. IR (KBr) 3399, 3350 (br) cm⁻¹. Ion SprayMS 459 (M+H)⁺; 457 (M−H)⁻. [α]_(D)=0 (c 0.35, MeOH). C₂₉H₃₄N₂O₃

analysis: calculated found C 75.95 76.19 H 7.47 7.37 N 6.11 6.27

EXAMPLE 86 Preparation of(2S)-(+)-3-[(2S,4S)-4-(8-Methoxynaphth-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(8-methoxynaphth-2-yl)-2-methylpiperidine (0.120 g, 0.468mmol, prepared in example 85) and (2S)-4-glycidyloxy-2-methylindole(0.095 g, 0.468 mmol) in MeOH (6 mL) was heated at reflux for 16 h andthen cooled and evaporated. The residue was purified using silica gelchromatography [1.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free baseof the final title compound as an off-white foam (0.076 g, 35%). Theoxalate salt was prepared with 1 equiv. of oxalic acid in EtOAc. mp(oxalate) 144–147° C. (dec.). IR (KBr) 3402, 3350 (br) cm⁻¹. Ion SprayMS 459 (M+H)⁺; 457 (M−H)⁻. [α]_(D)=25.48 (c 0.47, MeOH).C₂₉H₃₄N₂O₃.C₂H₂O₄.0.2C₄H₈O₂

analysis: calculated found C 67.45 67.25 H 6.69 6.88 N 4.95 4.97

EXAMPLE 87 Preparation of(2S)-(−)-3-[(2S,4R)-4-(8-Methoxynaphth-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(8-methoxynaphth-2-yl)-2-methylpiperidine (0.700 g, 2.74mmol, example 85) and (2S)-4-glycidyloxy-2-methylindole (0.557 g, 2.74mmol) in MeOH (35 mL) was heated at reflux for 24 h and then cooled andevaporated. The residue was purified using silica gel chromatography[1.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base of the finaltitle compound as a light green foam (0.414 g, 33%). The oxalate saltwas prepared with 1 equiv. of oxalic acid in EtOAc. IR (CHCl₃) 3474,3350 (br) cm⁻¹. Ion Spray MS 459 (M+H)⁺; 457 (M−H)⁻ [α]_(D)=−4.13 (c0.48, MeOH). C₂₉H₃₄N₂O₃.0.3CH₂Cl₂

analysis: calculated found C 72.70 72.81 H 7.20 7.33 N 5.79 6.11

EXAMPLE 88 Preparation of (2S)-(+)-3-[(2R,4S)-4-(8-Methoxynaphth-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(8-methoxynaphth-2-yl)-2-methylpiperidine (0.700 g, 2.74mmol, prepared in example 85) and (2S)-4–1.5 glycidyloxy-2-methylindole(0.557 g, 2.74 mmol) in MeOH (35 mL) was heated at reflux for 24 h andthen cooled and evaporated. The residue was purified using silica gelchromatography [1.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free baseof the title compound as a light green foam (0.579 g, 46%). The oxalatesalt was prepared with 1 equiv. of oxalic acid in EtOAc. IR (CHCl₃)3474, 3350 (br) cm⁻¹. Ion Spray MS 459 (M+H)⁺; 457 (M−H)⁻. [α]_(D)=12.00(c 0.50, MeOH). C₂₉H₃₄N₂O₃.C₂H₂O₄

analysis: calculated found C 67.87 68.13 H 6.61 6.87 N 5.11 4.97

EXAMPLE 89 Preparation of(2S)-(+)-1-(1H-2-Carboxamidoindol-4-yl)oxy-3-[4-(6-fluorobenzo[b]thiophen-2-yl)piperidinyl]-2-propanoloxalate

Preparation ofN-t-Butoxycarbonyl4-(6-fluorobenzo[b]thiophen-2-yl))-4-piperidinol.

Scheme IA, Step A: To a solution of 4- and 6-fluorobenzo[b]thiophene(1.70 g, 11.2 mmol) in dry THF (50 mL) at −78° C. was added 1.6 M n-BuLiin hexanes (9.08 mL, 14.5 mmol). The solution was stirred at −78° C. for35 min. N-t-Butoxycarbonyl-4-piperidone (2.67 g, 15.6 mmol) dissolved inTHF (10 mL) was added via a cannula at −78° C. The reaction mixture waskept at −78° C. for 1.5 h then allowed to warm to room temperature. Thereaction was then quenched with 150 mL of saturated aqueous NH₄Clsolution. The mixture was extracted (3×300 mL) with EtOAc. The combinedorganic layers were dried over MgSO₄ and filtered. The filtrate wasconcentrated and purified by medium pressure chromatography (silica gel,20% EtOAc/hexanes) to give the intermediate title compound as a whitefoam (2.24 g, 57%). mp 48–51° C. IR (CHCl₃) 3350 (br), 1682,1250 cm⁻¹.Ion Spray MS 352 (M+H)⁺; 234 (M−(BOC+H₂O)⁺; 278 (M−73)⁺ (base peak); 410(M+CH₃COO⁻)⁻.

Preparation of4-(6-Fluorobenzo[b]thiophen-2-yl)-1,2,5,6-tetrahydropyridine.

Scheme IA, Step B: To a solution ofN-t-butoxycarbonyl4-(6-fluorobenzo[b]thiophen-2-yl))-4-piperidinol (2.14g, 6.10 mmol) in dry CH₂Cl₂ (21 mL) at 0° C. was added 9 mL oftrifluoroacetic acid. The solution was stirred at 0° C. for 1.5 h. Thereaction was then quenched at room temperature with saturated aqueousNaHCO₃ solution (100 mL). The mixture was extracted (3×200 mL) with 10%MeOH in CH₂Cl₂. The combined organic layers were dried over MgSO₄ andconcentrated to give the intermediate title compound as an off-whitesolid (1.25 g, 88%). mp 155–157° C. IR (KBr) 3450 (br), 1248 cm⁻¹. IonSpray MS 234 (M+H)⁺.

Preparation of 4-(6-Fluorobenzo[b]thiophen-2-yl)piperidine.

Scheme IA, Step C: To a solution of4-(6-fluorobenzo[b]thiophen-2-yl)-1,2,5,6-tetrahydropyridine (0.850 g,3.64 mmol) in a 3:1 mixture of ethanol (30 mL) and2,2,2-trifluoroethanol (10 mL) was added 10% Pd/C (0.900 g). The blackslurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 1 day. The black slurry was then filtered over apad of diatomaceous earth and washed with ethanol. The filtrate wasconcentrated to provide the intermediate title compound as a white solid(0.735 g, 86%). mp 115–120° C. IR (KBr) 3350 (br), 1247 cm⁻¹. Ion SprayMS 236 (M+H)⁺.

Preparation of Final Title Compound.

Scheme IV, Step B: A solution of4-(6-fluorobenzo[b]thiophen-2-yl)piperidine (0.100 g, 0.425 mmol,prepared above) and (S)-4-(oxiranylmethoxy)indole-2-carboxamide (0.099g, 0.425 mmol) in MeOH (5 mL) was heated at reflux for 9 h and thencooled and evaporated. The residue was purified using silica gelchromatography [5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a white solid (0.156 g, 79%). The oxalate salt wasprepared with 1 equiv. of oxalic acid in EtOAc. mp (oxalate) 138–141° C(dec.). IR (KBr) 3300 (br), 1657 cm⁻¹. Ion Spray MS 468 (M+H)⁺; 466(M−H)⁻. [α]_(D)=5.73 (c 0.35, MeOH). C₂₅H₂₆FN₃O₃S

analysis: calculated found C 64.22 64.04 H 5.61 5.67 N 8.99 8.84

EXAMPLE 90 Preparation of(2S)-(−)-3-[(2R,4R)-4-(6-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1-H-indol-4-yl)oxy-2-propanoloxalate

Preparation ofN-t-Butoxycarbonyl-4-(6-fluorobenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol.

Scheme IA, Step A: To a solution of 4- and 6-fluorobenzo[b]thiophene(12.4 g, 81.7 mmol) in dry THF (415 mL) at −78° C. was added 1.6 Mn-BuLi in hexanes (56.4 mL, 90.2 mmol). The solution was stirred at −78°C. for 1.5 h. N-t-Butoxycarbonyl-2-methyl-4-piperidone (15.7 g, 73.5mmol) dissolved in THF (40 mL) was added via a cannula at −78° C. Thereaction mixture was stirred at −78° C. for 4 h. The reaction was thenquenched with 300 mL of saturated aqueous NH₄Cl solution. The mixturewas extracted (2×500 mL) with EtOAc. The combined organic layers werethen dried over MgSO₄ and filtered. The filtrate was concentrated andpurified by medium pressure chromatography (15% EtOAc/hexanes) to givethe intermediate title compound as a white foam (19.12 g, 71%). ¹HNMR(CDCl₃) 7.61 (dd, J=8.8, 4.9 Hz, 1H), 7.46 (dd, J=8.8, 2.4 Hz, 1H), 7.08(s, 1H), 7.06 (dt, J=8.8, 2.4 Hz, 1H), 4.44 (br m, 1H), 3.99–4.03 m,1H), 3.30–3.38 (br m, 1H), 2.16 (dd, J=14.2, 6.8 Hz, 1H), 1.89–2.05 (m,3H), 1.60 (br s, 1H), 1.46 (s, 9H), 1.38 (d, J=7.3 Hz, 3H).

Preparation of(±)-cis-4-(6-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl4-(6-fluorobenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(7.14 g, 19.5 mmol) in dry CH₂Cl₂ (63 mL) at 0° C. was added 27 mL oftrifluoroacetic acid. The solution was stirred at 0° C. for 2 h. Thereaction was then quenched at room temperature with saturated aqueousNaHCO₃ solution (350 mL). The mixture was extracted (2×500 mL) withCH₂Cl₂. The combined organic layers were dried over MgSO₄ andconcentrated to yield 4.48 g of crude regioisomeric olefins. To asolution of the crude olefins (4.48 g) in a 3:1 mixture of ethanol (150mL) and 2,2,2-trifluoroethanol (50 mL) was added 10% Pd/C (4.50 g). Theblack slurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 15 h. The black slurry was then filtered over apad of diatomaceous earth and washed with ethanol. The filtrate wasconcentrated, and the residue was purified by medium pressurechromatography [silica gel, 5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give theintermediate title compound as a brown solid (1.87 g, 38%). mp 34–37° C.IR (KBr) 3400 (br), 3235, 1237 cm⁻¹. Ion Spray MS 250 (M+H)⁺.

Preparation of(±)-trans-4-(6-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-(6-fluorobenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(7.14 g, 19.5 mmol) in dry CH₂Cl₂ (63 mL) at 0° C. was added 27 mL oftrifluoroacetic acid. The solution was stirred at 0° C. for 2 h. Thereaction was then quenched at room temperature with saturated aqueousNaHCO₃ solution (350 mL). The mixture was extracted (2×500 mL) withCH₂Cl₂. The combined organic layers were dried over MgSO₄ andconcentrated to yield 4.48 g of crude regioisomeric olefins. To asolution of the crude olefins (4.48 g) in a 3:1 mixture of ethanol (150mL) and 2,2,2-trifluoroethanol (50 mL) was added 10% Pd/C (4.50 g). Theblack slurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 15 h. The black slurry was then filtered over apad of diatomaceous earth and washed with ethanol. The filtrate wasconcentrated, and the residue was purified by medium pressurechromatography [silica gel, 5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to theintermediate title compound as a brown solid (1.20 g, 25%). IR (CHCl₃)1251 cm⁻¹. Ion Spray MS 250 (M+H)⁺.

Preparation of Final Title Compound.

Scheme IV, Step B: A solution of(±)-cis-4-(6-fluorobenzo[b]-thiophen-2-yl)-2-methylpiperidine (0.200 g,0.802 mmol) and (S)-4-(oxiranylmethoxy)indole (0.152 g, 0.802 mmol) inMeOH (10 mL) was heated at reflux for 23 h and then cooled andevaporated. The residue was purified using silica gel chromatography [1%(2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base of the final titlecompound as a white foam (0.166 g,47%). The oxalate salt was preparedwith 1 equiv. of oxalic acid in EtOAc. IR (KBr) 3407, 3300 (br), 1246cm⁻¹. Ion Spray MS 439 (M+H)⁺; 437 (M−H)⁻; 497 (M+CH₃COO⁻)⁻.[α]_(D)=−11.49 (c 0.52, MeOH). C₂₅H₂₇FN₂O₂S.C₂H₂O₄

analysis: calculated found C 61.35 61.49 H 5.53 5.51 N 5.30 5.36

EXAMPLE 91 Preparation of(2S)-(+)-3-[(2S,4S)-4-(6-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(6-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200 g,0.802 mmol, prepared in example 90) and (S)-4-(oxiranylmethoxy)indole(0.152 g, 0.802 mmol) in MeOH (10 mL) was heated at reflux for 23 h andthen cooled and evaporated. The residue was purified using silica gelchromatography [1% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a white foam (0.123 g, 35%). The oxalate salt wasprepared with 1 equiv. of oxalic acid in EtOAc. IR (KBr) 3405, 3300(br), 1246 cm⁻¹. Ion Spray MS 439 (M+H)⁺; 437 (M−H)⁻; 497 (M+CH₃COO⁻)⁻.[α]_(D)=27.71 (c 0.43, MeOH). C₂₅H₂₇FN₂O₂S.C₂H₂O₄

analysis: calculated found C 61.35 61.47 H 5.53 5.75 N 5.30 5.17

EXAMPLE 92 Preparation of(2S)-3-[(2S,4R)-4-(6-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(6-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.194 g,0.779 mmol, prepared in example 90) and (S)-4-(oxiranylmethoxy)indole(0.147 g, 0.779 mmol) in MeOH (10 mL) was heated at reflux for 20 h andthen cooled and evaporated. The residue was purified using silica gelchromatography [1% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a white foam (0.142 g, 41%). The oxalate salt wasprepared with 1 equiv. of oxalic acid in EtOAc. mp (oxalate) 113–116° C.IR (KBr) 3405, 3300 (br), 1246 cm⁻¹. Ion Spray MS 439 (M+H)⁺; 437(M−H)⁻. [α]_(D)=0 (c 0.56, MeOH). C₂₅H₂₇FN₂O₂S.C₂H₂O₄

analysis: calculated found C 61.35 61.07 H 5.53 5.27 N 5.30 5.22

EXAMPLE 93 Preparation of(2S)-(+)-3-[(2R,4S)-4-(6-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-indol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(6-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.194 g,0.779 mmol, prepared in example 90) and (S)-4-(oxiranylmethoxy)indole(0.147 g, 0.779 mmol) in MeOH (10 mL) was heated at reflux for 20 h andthen cooled and evaporated. The residue was purified using silica gelchromatography [1% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a white foam (0.150 g, 44%). The oxalate salt wasprepared with 1 equiv. of oxalic acid in EtOAc. mp (oxalate) 107–110° C.IR (KBr) 3408, 3300 (br), 1246 cm⁻¹. Ion Spray MS 439 (M+H)⁺; 437(M−H)⁻; 497 (M+CH₃COO⁻)⁻. [α]_(D)=14.79 (c 0.54, MeOH).C₂₅H₂₇FN₂O₂S.C₂H₂O₄

analysis: calculated found C 61.35 61.30 H 5.53 5.58 N 5.30 5.18

EXAMPLE 94 Preparation of(2S)-(+)-3-[4-(6-Fluorobenzo[b]thiophen-2-yl)piperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of4-(6-fluorobenzo[b]thiophen-2-yl)piperidine (0.100 g, 0.425 mmol,prepared in example 89) and (2S)-4-glycidyloxy-2-methylindole (0.086 g,0.425 mmol) in MeOH (5 mL) was heated at reflux for 9 h and then cooledand evaporated. The residue was purified using silica gel chromatography[1% (10% conc. NH₄OH in MeOH)/CH₂Cl₂] to give the free base of the titlecompound as a green foam (0.159 g, 85%). The oxalate salt was preparedwith 1 equiv. of oxalic acid in EtOAc. IR (CHCl₃) 3474, 3350 (br), 1249cm⁻¹. Ion Spray MS 439 (M+H)⁺; 437 (M−H)⁻; 497 (M+CH₃COO⁻)⁻.[α]_(D)=7.80 (c 0.51, MeOH). C₂₅H₂₇FN₂O₂S.C₂H₂O₄

analysis: calculated found C 61.35 61.10 H 5.53 5.72 N 5.30 5.08

EXAMPLE 95 Preparation of(2S)-(−)-3-[(2R,4R)-4-(6-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(6-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200 g,0.802 mmol, prepared in example 90) and(2S)-4-glycidyloxy-2-methylindole (0.163 g, 0.802 mmol) in MeOH (10 mL)was heated at reflux for 21 h and then cooled and evaporated. Theresidue was purified using silica gel chromatography [2% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the title compound as anoff-white foam (0.154 g, 42%). The oxalate salt was prepared with 1equiv. of oxalic acid in EtOAc. IR (CHCl₃) 3474, 3350 (br), 1249 cm⁻¹.Ion Spray MS 453 (M+H)⁺; 451 (M−H)⁻ 511 (M+CH₃COO⁻)⁻. [α]_(D)=−7.45 (c0.54, MeOH). C₂₆H₂₉FN₂O₂S.C₂H₂O₄

analysis: calculated found C 61.98 62.05 H 5.76 5.69 N 5.16 5.45

EXAMPLE 96 Preparation of(2S)-(+)-3-[(2S,4S)-4-(6-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(6-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200 g,0.802 mmol, prepared in example 90) and(2S)-4-glycidyloxy-2-methylindole (0.163 g, 0.802 mmol) in MeOH (10 mL)was heated at reflux for 21 h and then cooled and evaporated. Theresidue was purified using silica gel chromatography [2% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the title compound as anoff-white foam (0.141 g, 39%). The oxalate salt was prepared with 1equiv. of oxalic acid in EtOAc. mp (oxalate) 105–108° C. (dec.). IR(CHCl₃) 3474, 3350 (br), 1250 cm⁻¹. Ion Spray MS 453 (M+H)⁺; 451 (M−H)⁻511 (M+CH₃COO⁻)⁻. [α]_(D)=27.86 (c 0.36, MeOH). C₂₆H₂₉FN₂O₂S

analysis: calculated found C 69.00 69.23 H 6.46 6.63 N 6.19 6.14

EXAMPLE 97 Preparation of (2S)-3-[(2S,4R)-4-(6-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol-4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(6-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200 g,0.802 mmol, prepared in example 90) and(2S)-4-glycidyloxy-2-methylindole (0.163 g, 0.802 mmol) in MeOH (10 mL)was heated at reflux for 20 h and then cooled and evaporated. Theresidue was purified using silica gel chromatography [1% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the title compound as a whitefoam (0.174 g, 48%). The oxalate salt was prepared with 1 equiv. ofoxalic acid in EtOAc. IR (CHCl₃) 3474, 3350 (br), 1249 cm⁻¹. Ion SprayMS 453 (M+H)⁺; 451 (M−H)⁻. [α]_(D)=0 (c 0.48, MeOH).C₂₆H₂₉FN₂O₂S.0.1CH₂Cl₂

analysis: calculated found C 67.99 68.09 H 6.38 6.57 N 6.08 5.84

EXAMPLE 98 Preparation of(2S)-(+)-3-[(2R,4S)-4-(6-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-1-(1H-2-methylindol4-yl)oxy-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(6-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200 g,0.802 mmol, prepared in example 90) and(2S)-4-glycidyloxy-2-methylindole (0.163 g, 0.802 mmol) in MeOH (10 mL)was heated at reflux for 20 h and then cooled and evaporated. Theresidue was purified using silica gel chromatography [1% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the free base of the title compound as a whitefoam (0.158 g, 43%). The oxalate salt was prepared with 1 equiv. ofoxalic acid in EtOAc. IR (CHCl₃) 3474, 3350 (br), 1250 cm⁻¹. Ion SprayMS 453 (M+H)⁺; 451 (M−H)⁻. [α]_(D)=11.95 (c 0.50, MeOH).C₂₆H₂₉FN₂O₂S.0.1CH₂Cl₂

analysis: calculated found C 67.99 68.27 H 6.38 6.41 N 6.08 6.14

EXAMPLE 99 Preparation of(2S)-1-(1H-2-Carboxamidoindol-4-yl)oxy-3-[(2R,4R)-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-2-propanoloxalate

Preparation ofN-t-Butoxycarbonyl-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol.

Scheme IA, Step A: To a solution of 4-methoxybenzo[b]thiophene (7.70 g,46.9 mmol) in dry THF (230 mL) at −78° C. was added 1.6 M n-BuLi inhexanes (32.2 mL, 51.6 mmol). The solution was stirred at −78° C. for 45min. N-t-Butoxycarbonyl-2-methyl-4-piperidone (6.00 g, 28.1 mmol)dissolved in THF (40 mL) was added via a cannula at −78° C. The reactionmixture was slowly warmed to room temperature and stirred for 16 h. Thereaction was then quenched with 600 mL of saturated aqueous NH₄Clsolution. The mixture was extracted (1×1 L) with EtOAc. The combinedorganic layers were then dried over MgSO₄ and filtered. The filtrate wasconcentrated and purified by medium pressure chromatography (silica gel,25% Et₂O/hexanes) to give the intermediate title compound as a whitefoam (5.06 g, 48%). mp 73–76° C. IR (CHCl₃) 3474, 3350 (br) cm⁻¹. IR(CHCl₃) 3350 (br), 1680 cm⁻¹. Ion Spray MS 378 (M+H)⁺; 260(M−(Boc+H₂O))⁺; 304 (M−74)⁺ (base peak); 436 (M+CH₃COO⁻)⁻.

Preparation of(±)-cis-4-(4-Methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl4-(4-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(5.00 g, 13.2 mmol) in dry CH₂Cl₂ (92 mL) at 0° C. was added 18 mL oftrifluoroacetic acid. The resulting purple solution was stirred at 0° C.for 1 h 20 min. The reaction was then quenched at room temperature withsaturated aqueous NaHCO₃ solution (220 mL). The mixture was extracted(2×500 mL) with CH₂Cl₂. The combined organic layers were washed (1×100mL) with brine, dried over MgSO₄, and concentrated to yield 3.67 g ofcrude regioisomeric olefins. To a solution of the crude olefins (3.67 g)in a 3:1 mixture of ethanol (99 mL) and 2,2,2-trifluoroethanol (33 mL)was added 10% Pd/C (3.50 g). The black slurry was stirred vigorously atroom temperature under hydrogen (balloon pressure) for 24 h. The blackslurry was then filtered over a pad of diatomaceous earth and washedwith ethanol. The filtrate was concentrated, and the residue waspurified by medium pressure chromatography [silica gel, 5% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the intermediate title compound as an orange solid(1.87 g, 54%). mp 70–73° C. IR (KBr) 3436 (br), 3246 cm⁻¹. Ion Spray MS262 (M+H)⁺.

Preparation of(±)-trans-4-(4-Methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, Steps B and C: To a solution ofN-t-butoxycarbonyl-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(5.00 g, 13.2 mmol) in dry CH₂Cl₂ (92 mL) at 0° C. was added 18 mL oftrifluoroacetic acid. The resulting purple solution was stirred at 0° C.for 1 h 20 min. The reaction was then quenched at room temperature withsaturated aqueous NaHCO₃ solution (220 mL). The mixture was extracted(2×500 mL) with CH₂Cl₂. The combined organic layers were washed (1×100mL) with brine, dried over MgSO₄, and concentrated to yield 3.67 g ofcrude regioisomeric olefins. To a solution of the crude olefins (3.67 g)in a 3:1 mixture of ethanol (99 mL) and 2,2,2-trifluoroethanol (33 mL)was added 10% Pd/C (3.50 g). The black slurry was stirred vigorously atroom temperature under hydrogen (balloon pressure) for 24 h. The blackslurry was then filtered over a pad of diatomaceous earth and washedwith ethanol. The filtrate was concentrated, and the residue waspurified by medium pressure chromatography [silica gel, 5% (2.0 M NH₃ inMeOH)/CH₂Cl₂] to give the intermediate title compound as an orange solid(0.580 g, 17%). mp 76–78° C. IR (KBr) 3400 (br), 3223 cm⁻¹. Ion Spray MS262 (M+H)⁺.

Preparation of Final Title Compound.

Scheme IV, Step B: A solution of(±)-cis-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.134 g,0.527 mmol) and (S)-4-(oxiranylmethoxy)indole-2-carboxamide (0.122 g,0.527 mmol) in MeOH (7 mL) was heated at reflux for 8 h and then cooledand evaporated. The residue was purified using silica gel chromatography[4.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base of the titlecompound as an off-white foam (0.119 g, 46%). The oxalate salt wasprepared with I equiv. of oxalic acid in EtOAc. mp (oxalate) 172° C.(dec.). IR (KBr) 3300 (br), 1653 cm⁻¹. Ion Spray MS 494 (M+H)⁺; 492(M−H)⁻. [α]_(D) (oxalate)=0 (c 0.34, DMSO). C₂₇H₃₁N₃O₄S.C₂H₂O₄.0.3C₄H₈O₂

analysis: calculated found C 59.45 59.06 H 5.85 5.73 N 6.89 6.73

EXAMPLE 100 Preparation of(2S)-(+)-1-(1H-2-Carboxamidoindol-4-yl)oxy-3-[(2S,4S)-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.134 g,0.527 mmol, prepared in example 99) and(S)-4-(oxiranylmethoxy)indole-2-carboxamide (0.122 g, 0.527 mmol) inMeOH (7 mL) was heated at reflux for 8 h and then cooled and evaporated.The residue was purified using silica gel chromatography [4.5% (2.0 MNH₃ in MeOH)/CH₂Cl₂] to give the free base of the title compound as anoff-white foam (0.102 g, 39%). The oxalate salt was prepared with 1equiv. of oxalic acid in EtOAc. mp (oxalate) 162 (dec.). IR (KBr) 3300(br), 1653 cm⁻¹. Ion Spray MS 494 (M+H)⁺; 492 (M−H)⁻. [α]_(D)(oxalate)=5.26 (c 0.38, DMSO). C₂₇H₃₁N₃O₄S.C₂H₂O₄.0.3C₄H₈O₂

analysis: calculated found C 59.45 59.08 H 5.85 5.67 N 6.89 6.84

EXAMPLE 101 Preparation of(2S)-1-(1H-2-Carboxamidoindol-4-yl)oxy-3-[(2S,4R)-4-(4-5methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.063g, 0.239 mmol, prepared in example 99) and(S)-4-(oxiranylmethoxy)indole-2-carboxamide (0.056 g, 0.239 mmol) inMeOH (3 mL) was heated at reflux for 8 h and then cooled and evaporated.The residue was purified using silica gel chromatography [6% (2.0 M NH₃in MeOH)/CH₂Cl₂] to give the free base of the title compound as anoff-white foam (0.041 g, 35%). The oxalate salt was prepared with 1equiv. of oxalic acid in EtOAc. mp (oxalate) 170° C. (dec.). IR (KBr)3300 (br), 1658 cm⁻¹. Ion Spray MS 494 (M+H)⁺; 492 (M−H)⁻.C₂₇H₃₁N₃O₄S.C₂H₂O₄

analysis: calculated found C 59.68 59.47 H 5.70 5.51 N 7.20 7.08

EXAMPLE 102 Preparation of(2S)-1-(1H-2-Carboxamidoindol-4-yl)oxy-3-[(2R,4S)-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.063g, 0.239 mmol, prepared in example 99) and(S)-4-(oxiranylmethoxy)indole-2-carboxamide (0.056 g, 0.239 mmol) inMeOH (3 mL) was heated at reflux for 8 h and then cooled and evaporated.The residue was purified using silica gel chromatography [6% (2.0 M NH₃in MeOH)/CH₂Cl₂] to give the free base of the title compound as anoff-white foam (0.044 g, 37%). The oxalate salt was prepared with 1equiv. of oxalic acid in EtOAc. mp 158–161° C. IR (KBr) 3300 (br), 1658cm⁻¹. Ion Spray MS 494 (M+H)⁺; 492 (M−H)⁻. C₂₇H₃₁N₃O₄S.0.1CH₂Cl₂

analysis: calculated found C 64.82 64.68 H 6.26 6.41 N 8.37 8.52

EXAMPLE 103 Preparation of(2S)-(−)-1-(1H-Indol-4-yl)oxy-3-[(2R,4R)-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200 g,0.765 mmol, prepared in example 99) and (S)-4-(oxiranylmethoxy)indole(0.145 g, 0.765 mmol) in MeOH (10 mL) was heated at reflux for 10 h andthen cooled and evaporated. The residue was purified using silica gelchromatography [1% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a white foam (0.137 g, 40%). The oxalate salt wasprepared with 1 equiv. of oxalic acid in EtOAc. mp (oxalate) 136–139° C.IR (KBr) 3409, 3350 (br) cm⁻¹. Ion Spray MS 451 (M+H)⁺; 449 (M−H)⁻; 509(M+CH₃COO⁻)⁻. [α]_(D)=−7.37 (c 0.54, MeOH. C₂₆H₃₀N₂O₃S.C₂H₂O₄

analysis: calculated found C 62.21 62.07 H 5.97 6.10 N 5.18 5.03

EXAMPLE 104 Preparation of(2S)-(+)-1-(1H-Indol-4-yl)oxy-3-[(2S,4S)-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-cis-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.200 g,0.765 mmol, prepared in example 99) and (S)-4-(oxiranylmethoxy)indole(0.145 g, 0.765 mmol) in MeOH (10 mL) was heated at reflux for 10 h andthen cooled and evaporated. The residue was purified using silica gelchromatography [1% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a white foam (0.143 g, 42%). The oxalate salt wasprepared with 1 equiv. of oxalic acid in EtOAc. mp (oxalate) 134–137° C.IR (KBr) 3412, 3350 (br) cm⁻¹. Ion Spray MS 451 (M+H)⁺; 449 (M−H)⁻.[α]_(D)=4.37 (c 0.46, MeOH). C₂₆H₃₀N₂O₃S.C₂H₂O₄

analysis: calculated found C 62.21 62.13 H 5.97 6.07 N 5.18 5.14

EXAMPLE 105 Preparation of(25)-1-(1H-Indol-4-yl)oxy-3-[(2S,4R)-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.192g, 0.734 mmol, prepared in example 99) and (S)-4-(oxiranylmethoxy)indole(0.139 g, 0.734 mmol) in MeOH (10 mL) was heated at reflux for 10 h andthen cooled and evaporated. The residue was purified using silica gelchromatography [1% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a white foam (0.146 g, 44%). The oxalate salt wasprepared with 1 equiv. of oxalic acid. mp (oxalate) 112–115° C. IR(CHCl₃) 3409, 3350 (br) cm⁻¹. Ion Spray MS 451 (M+H)⁺; 449 (M−H)⁻.[α]_(D)=0 (c 0.53, MeOH). C₂₆H₃₀N₂O₃S

analysis: calculated found C 69.30 69.55 H 6.71 6.63 N 6.22 6.16In addition, the corresponding hydrochloride salt and correspondingsuccinate salts were prepared from 1 equivalent of hydrochloric acid and1 equivalent of succinic acid respectively.

EXAMPLE 106 Preparation of(2S)-(+)-1-(1H-Indol-4-yl)oxy-3-[(2R,4S)-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidinyl]-2-propanoloxalate

Scheme IV, Step B: A solution of(±)-trans-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.192g, 0.734 mmol, prepared in example 99) and (S)4-(oxiranylmethoxy)indole(0.139 g, 0.734 mmol) in MeOH (10 mL) was heated at reflux for 10 h andthen cooled and evaporated. The residue was purified using silica gelchromatography [1% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the free base ofthe title compound as a white foam (0.149 g, 45%). The oxalate salt wasprepared with 1 equiv. of oxalic acid in EtOAc. mp (oxalate) 120–123° C.IR (CHCl₃) 3410, 3350 (br) cm⁻¹. Ion Spray MS 453 (M+H)⁺; 451 (M−H)⁻.[α]_(D)=11.17 (c 0.54, MeOH). C₂₆H₃₀N₂O₃S.1.2C₂H₂O₄.0.1 C₄H₈O₂

analysis: calculated found C 60.96 60.61 H 5.90 5.57 N 4.94 5.03

EXAMPLE 107 Preparation ofcis-(2S)-(−)-1-(4-Indolyioxy)-3-(4-(4-fluorobenzothiazol-2-yl)-2-methylpiperidin-1-yl)-2-propanolOxalate.

Preparation of4-(4-Fluorobenzothiazol-2-yl)-1-(t-butyloxycarbonyl)-2-methyl-1,2,3,6-tetrahydropyridine

Scheme IA, Step A: To a mixture of 2-chloro-4-fluorobenzothiazole (1.012g, 5.39 mmol) in 1,4-dioxane (60 mL) was added2-methyl-4-trifluoromethylsulfonyl-1-(t-butyloxycarbonyl)-1,2,3,6-tetrahydropyridine(1.956 g, 5.66 mmol), hexamethylditin (1.767 g, 5.39 mmol),tetrakis(triphenylphosphine)-palladium (0.312 g, 0.269 mmol) and lithiumchloride (0.686 g, 16.2 mmol). The mixture was heated at reflux for 20hours, then cooled to 20° C. and diluted with saturated potassiumfluoride and ethyl acetate. The mixture was stirred for 2 hours thenpartitioned and the organic layer was washed with brine, dried oversodium sulfate and evaporated. The residue was chromatographed oversilica gel (hexanes/50% ethyl acetate in hexanes gradient elution) togive the intermediate title compound as a yellow amorphous solid (1.227g, 72%). FDMS m/e=349 (M⁺+1).

Preparation of4-(4-Fluorobenzothiazol-2-yl)-2-methyl-1,2,3,6-tetrahydropyridine.

Scheme IIA, Step B: To a mixture of4-(4-fluorobenzothiazol-2-yl))-1-(t-butyloxycarbonyl)-2-methyl-1,2,3,6-tetrahydropyridine(1.207 g, 3.81 mmol) in dichloromethane (10 mL) at 0° C. was addedtrifluoroacetic acid (10 mL). The mixture was stirred at 0° C. for 30minutes, then at 20° C. for 30 minutes. The mixture was diluted with 2 Nsodium hydroxide and extracted 3 times with ethyl acetate. The combinedorganic layers were dried over sodium sulfate, then filtered andevaporated. The residue was chromatographed over silica gel(dichloromethane/10% methanol 1% ammonium hydroxide in dichloromethanegradient elution) to give the intermediate title compound as a yellowoil (0.794 g, 84%). FDMS m/e=249 (M⁺+1).

Preparation of Cis- andTrans-4-(4-Fluorobenzothiazol-2-yl)-2-methylpiperidine.

Scheme IIA, Step C: To a mixture of4-(4-fluorobenzothiazol-2-yl))-2-methyl-1,2,3,6-tetrahydropyridine(0.691 g, 3.04 mmol) in ethanol (20 mL) was added platinum oxide (0.03g). The mixture was hydrogenated at one atmosphere for 20 hours. Themixture was carefully filtered and evaporated to give the titlecompounds as a pair of yellow oils.

-   Cis: 0.267 g, 34%. FDMS m/e=251 (M⁺+1).-   Trans: 0.243 g, 31%. FDMS m/e=251 (M⁺+1).    Preparation of Final Title Compound.

Scheme IV, Step B: A solutioncis-4-(4-fluorobenzothiazol-2-yl))-2-methylpiperidine (0.130 g, 0.519mmol, isomer 1) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.098 g,0.519 mmol) in methanol (5 mL) was heated at reflux for 18 hours andthen cooled and evaporated. The residue was purified by silica gelchromatography (dichloromethane/2% methanol 0.2% anhydrous ammonia indichloromethane gradient elution) to givecis-(2S)-1-(4-indolyloxy)-3-(4-(4-fluorobenzothiazol-2-yl)-2-methylpiperidin-1-yl)-2-propanolas two white amorphous solids. The oxalate salts were prepared to givethe title compounds.

-   Isomer 1 (0.114 g, 50%, free base). FDMS m/e=440 (M⁺+1 of free    base). [α]_(D)=−9.13 (c 0.438, methanol).    C₂₄H₂₆FN₃O₂S.0.9C₂H₂O₄.0.1H₂O

analysis: calculated found C 59.32 59.56 H 5.40 5.80 N 8.04 7.75

-   Isomer 2 (0.110 g, 48%, free base). FDMS m/e=440 (M⁺+1 of free    base). [α]_(D)=−3.93 (c 0.509, methanol).    C₂₄H₂₆FN₃O₂S.0.9C₂H₂O₄.0.1H₂O

analysis: calculated found C 59.32 59.71 H 5.40 5.31 N 8.04 8.10

EXAMPLE 108 Preparation oftrans-(2S)-(−)-1-(4-Indolyloxy)-3-(4-(4-fluorobenzothiazol-2-yl)-2-methylpiperidin-1-yl)-2-pronpanolOxalate.

Scheme IV, Step B: A solution oftrans-4-(4-fluorobenzothiazol-2-yl))-2-methylpiperidine (0.121 g, 0.483mmol, isomer 1) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.091 g,0.483 mmol) in methanol (5 mL) was heated at reflux for 18 hours andthen cooled and evaporated. The residue was purified by silica gelchromatography (dichloromethane/2% methanol 0.2% anhydrous ammonia indichloromethane gradient elution) to give the free base of the titlecompounds as two white amorphous solids. The oxalate salts were preparedto give the title compounds.

-   Isomer 1 (0.081 g, 38%, free base). FDMS m/e=440 (M⁺+1 of free    base). [α]_(D)=−7.98 (c 0.501, methanol).    C₂₄H₂₆FN₃O₂S.2.0C₂H₂O₄.0.7H₂O

analysis: calculated found C 53.19 52.82 H 5.01 4.61 N 6.65 6.89

-   Isomer 2 (0.92 g, 44%, free base). FDMS m/e=440 (M⁺+1 of free base).    [α]_(D)=−7.86 (c 0.509, methanol). C₂₄H₂₆FN₃O₂S.C₂H₂O₄.

analysis: calculated found C 58.97 59.13 H 5.33 5.27 N 7.93 7.85

EXAMPLE 109 Preparation ofcis-(2S)-1-(4-Indolyloxy)-3-(4-(4-methylbenzothiazol-2-yl)-2-methylpiperidin-1-yl)-2-propanolOxalate.

Preparation of4-(4-Methylbenzothiazol-2-yl)-1-(t-butyloxycarbonyl)-2-methyl-1,2,3,6-tetrahydropyridine.

Scheme IIA, Step A: To a mixture of 2-chloro-4-methylbenzothiazole(1.052 g, 5.73 mmol) in 1,4-dioxane (60 mL) was added2-methyl-4-trifluoromethylsuffonyl-1-(t-butyloxycarbonyl)-1,2,3,6-tetrahydropyridine(2.077 g, 6.01 mmol), bis(trimethyltin) (1.876 g, 5.73 mmol),tetrakis(triphenylphosphine)-palladium (0.331 g, 0.286 mmol) and lithiumchloride (0.729 g, 17.2 mmol). The mixture was heated at reflux for 20hours then cooled to 20° C. and diluted with saturated potassiumfluoride and ethyl acetate. The mixture was stirred for 2 hours, thenpartitioned and the organic layer was washed with brine, dried oversodium sulfate and evaporated. The residue was chromatographed oversilica gel (hexanes/50% ethyl acetate in hexanes gradient elution) togive the intermediate title compound as a yellow amorphous solid (1.3 g,66%). FDMS m/e=345 (M⁺+1).

Preparation of4-(4-Methylbenzothiazol-2-yl)-2-methyl-1,2.3,6-tetrahydropyridine.

Scheme IIA, Step B: To a mixture of4-(4-methylbenzothiazol-2-yl)-1-(t-butyloxycarbonyl)-2-methyl-1,2,3,6-tetrahydropyridine(1.297 g, 3.77 mmol) in dichloromethane (12 mL) at 0° C. was addedtrifluoroacetic acid (12 mL). The mixture was stirred at 0° C. for 30minutes, then at 20° C. for 30 minutes. The mixture was diluted with 2 Nsodium hydroxide and extracted 3 times with ethyl acetate. The combinedorganic layers were dried over sodium sulfate, then filtered andevaporated. The residue was chromatographed over silica gel(dichloromethane/10% methanol 1% ammonium hydroxide in dichloromethanegradient elution) to give the intermediate title compound as a yellowoil (0.738 g, 85%). FDMS m/e=245 (M⁺+1).

Preparation of cis- andtrans-4-(4-Methylbenzothiazol-2-yl)-2-methylpiperidine.

Scheme IIA, Step C: To a mixture of4-(4-methylbenzothiazol-2-yl)-2-methyl-1,2,3,6-tetrahydropyridine (0.717g, 2.93 mmol) in methanol (25 mL) was added platinum oxide (0.7 g). Themixture was hydrogenated at one atmosphere for 20 hours. The mixture wascarefully filtered and evaporated to give the intermediate titlecompounds as a pair of yellow oils.

-   Cis: 0.194 g, 27%. FDMS m/e=246 (M⁺). C₁₄H₁₈N₂S.

analysis: calculated found C 68.25 68.45 H 7.36 7.60 N 11.37 11.48

-   Trans: 0.132 g, 18%. FDMS m/e=247 (M⁺+1). C₁₄H₁₈N₂S.

analysis: calculated found C 68.25 68.26 H 7.36 7.57 N 11.37 11.45Preparation of Final Title Compounds.

Scheme IV, Step B: A solutioncis-4-(4-methylbenzothiazol-2-yl)-2-methylpiperidine (0.098 g, 0.398mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.075 g, 0.398 mmol) inmethanol (4 mL) was heated at reflux for 18 hours and then cooled andevaporated. The residue was purified by silica gel chromatography(dichloromethane/5% methanol 0.5% ammonium hydroxide in dichloromethanegradient elution) to give the free base of the final title compounds astwo white amorphous solids. The oxalate salts were prepared to give thetitle compounds.

-   Isomer 1 (0.089 g, 50%, free base). FDMS m/e=436 (M⁺+1 of free    base). [α]_(D)=−14.73 (c 0.543, methanol). C₂₅H₂₉N₃O₂S.C₂H₂O₄.

analysis: calculated found C 61.70 61.52 H 5.94 5.85 N 7.99 7.74

-   Isomer 2 (0.076 g, 44%). Data for free base. FDMS m/e=436 (M⁺+1).    C₂₅H₂₉N₃O₂S.

analysis: calculated found C 68.94 69.14 H 6.71 6.91 N 9.65 9.60

EXAMPLE 110 Preparation oftrans-(2S)-1-(4-Indolyloxy)-3-(4-(4-methyl)benzothiazol-2-yl)-2-methylpiperidin-1-yl)-2-propanolOxalate

Scheme IV, Step B: A solutiontrans-4-(4-methylbenzothiazol-2-yl)-2-methylpiperidine (0.062 g, 0.252mmol, prepared in example 109) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole(0.048 g, 0.252 mmol) in methanol (3 mL) was heated at reflux for 18hours and then cooled and evaporated. The residue was purified by silicagel chromatography (dichloromethane/5% methanol 0.5% ammonium hydroxidein dichloromethane gradient elution) to give the free base of titlecompounds as two white amorphous solids. The oxalate salts were preparedto give the title compounds.

-   Isomer 1 (0.050 g, 45%). Data for free base. FDMS m/e=436 (M⁺+1).    C₂₅H₂₉N₃O₂S

analysis: calculated found C 68.94 69.15 H 6.71 6.52 N 9.65 9.46

-   Isomer 2 (0.52 g, 47%, free base). FDMS m/e=436 (M⁺+1 of free base).    [α]_(D)=−5.6 (c 0.357, methanol). C₂₅H₂₉N₃O₂S.0.9C₂H₂O₄.0.2H₂O.

analysis: calculated found C 61.87 62.23 H 6.05 6.33 N 8.08 7.98

EXAMPLE 111 Preparation ofcis-(2S)-(−)-1-(4-Indolyloxy)-3-((2-methyl-4-naphth-2-yl)piperidin-1-yl)-2-propanolmaleate.

Preparation of 1,2-Dimethyl4-hydroxy-4-(naphth-2-yl)piperidine.

Scheme I, Step A: t-Butyllithium (11 mL of a 1.7 M solution intetrahydrofuran, 18.8 mmol) was added to a solution of2-bromonaphthalene (1.77 g, 8.5 mmol) in tetrahydrofuran (60 mL) at −78°C. The reaction mixture was stirred at that temperature for 1.5 hoursand to it was then added dropwise a solution of1,2-dimethyl-4-piperidone (1.14 g, 8.9 mmol, prepared by methods wellknown to one of ordinary skill in the art) in tetrahydrofuran (10 mL).The reaction mixture was allowed to warm to room temperature. Themixture was then partitioned between ethyl acetate and water. The phaseswere separated and the aqueous phase was extracted well with ethylacetate. The combined organic phases were washed with brine, dried oversodium sulfate, and concentrated under reduced pressure to provide1,2-dimethyl-4-hydroxy4-(naphth-2-yl)piperidine (2.13 g, 98%) as a clearviscous oil. The crude product was taken on, to the next step withoutfurther purification.

Preparation of 1,2-dimethyl-4-(naphth-2-yl)-1,2,3,6-tetrahydropyridine.

Scheme I, Step B: A mixture of1,2-dimethyl-4-hydroxy-4-(naphth-2-yl)piperidine (2.13 g, 8.3 mmol) andp-toluenesulfonic acid monohydrate (3.17 g, 16.7 mmol) in toluene (45mL) was stirred for 12 hours at reflux. The reaction mixture was cooledto room temperature and partitioned between ethyl acetate and 2 N sodiumhydroxide. The combined organic phases were washed with brine, driedover sodium sulfate, and concentrated under reduced pressure. The cruderesidue was purified by flash chromatography (4% methanol indichloromethane, silica gel). Fractions containing product were combinedand concentrated under reduced pressure to provide1,2-dimethyl-4-(naphth-2-yl)-1,2,3,6-tetrahydropyridine (0.983 g, 50%pure) as an off-white, waxy solid.

Preparation of 1,2-dimethyl-4-(naphth-2-yl)piperidine.

Scheme I, Step C: A mixture of1,2-dimethyl-4-(naphth-2-yl)-1,2,3,6-tetrahydropyridine (0.983 g, 4.1mmol) and 0.1 g of 5% palladium on carbon in methanol (20 mL) wasstirred under a hydrogen atmosphere for 12 hours at room temperature.The mixture was then filtered through a bed of Celite and the filtrateconcentrated under reduced pressure to provide1,2-dimethyl-4-(naphth-2-yl)piperidine (0.890 g, 90% pure) as a clearoil.

Preparation of 2-methyl-4-(naphth-2-yl)piperidine.

Scheme I, Step D: To a solution of1,2-dimethyl-4-(naphth-2-yl)piperidine (0.89 g, 3.7 mmol) in1,2-dichloroethane (15 mL) was slowly added 1-chloroethyl chloroformate(1.2 mL, 11.2 mmol) at 0° C. The reaction mixture was allowed to warm toroom temperature and was subsequently heated at reflux for 12 hours. Thesolvent was evaporated under reduced pressure and the residue wasdissolved in 15 mL methanol. After stirring at reflux for 4 hours thereaction mixture was concentrated under reduced pressure and partitionedbetween ethyl acetate and 2 N sodium hydroxide. The phases wereseparated and the aqueous phase was extracted well with ethyl acetate.The combined organic phases were washed with brine, dried over sodiumsulfate, and concentrated under reduced pressure. The crude residue waspurified by radial chromatography (8% methanol in dichloromethane, 2 mmsilica gel plate) to provide 0.189 g (31%, based on the recoveredstarting material) of cis-Isomer 1 (R_(f) 0.26) as a tan oil and 0.159 g(26%, based on recovered starting material) of trans-Isomer (R_(f) 0.17)as a tan oil.

Alternative Preparation of 2-Methyl-4-(naphth-2-yl)piperidine.

Preparation of2-methyl-4-(naphth-2-yl)-1-phenoxycarbonyl-1,2,3,6-tetrahydropyridine.

Scheme II, Step A: n-Butyllithium (47.4 mL of a 1.6 M intetrahydrofuran, 75.9 mmol) was added to a solution of2-bromonaphthalene (15.0 g, 63.3 mmol) in tetrahydrofuran (350 mL) at−78° C. The reaction mixture was stirred at that temperature for 1.5hours and to it was then added dropwise a solution of triisopropylborate(19.0 mL, 82.2 mmol). The reaction mixture was allowed to warm to roomtemperature and stir for 12 hours. The mixture was then partitionedbetween ethyl acetate and saturated aqueous sodium chloride. The phaseswere separated and the aqueous phase was extracted well with ethylacetate. The combined organic phases were washed with brine, dried oversodium sulfate, and concentrated under reduced pressure. The residue wassonicated in a mixture of hexanes:ethyl acetate. The resultingsuspension was filtered to provide 2-naphthylboronic acid (8.28 g, 76%)as a white solid.

A mixture of the 2-naphthylboronic acid (3.71 g, 21.6 mmol),2-methyl-1-phenoxycarbonyl-4-trifluoromethanesulfonyloxy-1,2,3,6-tetrahydropyridine(5.60 g, 15.6 mmol, this reagent may be prepared by methods well knownto one of ordinary skill in the art), lithium chloride (1.96 g, 46.2mmol), tetrakis(triphenylphosphine)palladium(0) (0.712 g, 0.62 mmol),and 4 mL of 2 M aqueous sodium carbonate in tetrahydrofuran (40 mL) wasstirred at reflux for 12 hours. The reaction mixture was cooled to roomtemperature and then partitioned between ethyl acetate and 2 N sodiumhydroxide. The phases were separated and the aqueous phase was extractedwell with ethyl acetate. The combined organic phases were washed withbrine, dried over sodium sulfate, and concentrated under reducedpressure. The residue was purified by flash silica gel chromatography,eluting with 10:1 hexanes:ethyl acetate. Fractions containing productwere combined and concentrated under reduced pressure to provide2-methyl-4-(naphth-2-yl)-1-phenoxycarbonyl-1,2,3,6-tetrahydropyridine(4.26 g, 81%) as a waxy, white solid.

Preparation of 2-methyl-4-(naphth-2-yl)-1-(phenoxycarbonyl)piperidine.

Scheme II, Step B: A mixture of2-methyl-4-(naphth-2-yl)-1-phenoxycarbonyl-1,2,3,6-tetrahydropyridine(3.87 g, 11.3 mmol) and 5% palladium on carbon (0.2 g) in 50 mL ofmethanol was stirred under a hydrogen atmosphere for 12 hours at roomtemperature. The mixture was then filtered through a bed of Celite andthe filtrate was concentrated under reduced pressure to provide2-methyl-4-(naphth-2-yl)-1-(phenoxycarbonyl)piperidine. (3.42 g, 88%) asa clear oil.

Preparation of 2-methyl-4-(naphth-2-yl)piperidine.

Scheme II, Step C: A mixture of2-methyl-4-(naphth-2-yl)-1-phenoxycarbonylpiperidine (3.42 g, 9.9 mmol)and potassium hydroxide (59 g, 1.05 mol) in 150 mL of 50% water inisopropyl alcohol was stirred at reflux for about 72 hours. The reactionmixture was cooled to room temperature and partitioned between ethylacetate and 2 N sodium hydroxide. The phases were separated and theaqueous phase was extracted well with ethyl acetate. The combinedorganic phases were washed with brine, dried over sodium sulfate, andconcentrated under reduced pressure. The crude residue was purified byflash chromatography (8% methanol in dichloromethane, silica gel) toprovide 0.872 g (39%) of cis-lsomer(Rf 0.26) as a tan oil and 0.368 g(16%) of trans-Isomer (Rf 0.17) as a tan oil.

Preparation of Final Title Compound.

Scheme IV, Step B: A solution of (S)-(+)-4-(oxiranylmethoxy)-1H-indole(0.149 g, 0.79 mmol) and 2-methyl-4-(naphth-2-yl)piperidine (0.177 g,0.79 mmol, cis-isomer) in methanol was stirred at reflux for 12 h. Themixture was cooled to room temperature and the solvent was evaporated.The crude residue was purified by radial chromatography (2% methanol indichloromethane, 2 mm silica gel plate) providing 0.130 g (40%) of afree base of the title compound (Rf 0.65) as a white foam. The maleatesalt was prepared to provide the title compound.

-   [α]_(D)=−15.02 (c 0.53, methanol).-   FDMS m/e=414 (M⁺ of free base). C₂₇H₃₀N₂O₂.C₄H₄O₄

analysis: calculated found C 70.31 70.05 H 6.28 6.47 N 5.29 5.26

EXAMPLE 112 Preparation ofcis-(2S)-(−)-1-(4-Indolyloxy)-3-((2-methyl-4-naphth-2-yl)piperidin-1-yl)-2-propanolmaleate

Scheme IV, Step B: A solution of (S)-(+)-4-(oxiranylmethoxy)-1H-indole(0.149 g, 0.79 mmol) and 2-methyl-4-(naphth-2-yl) piperidine (0.177 g,0.79 mmol, cis-Isomer, prepared in example 111 ) in methanol was stirredat reflux for 12 h. The mixture was cooled to room temperature and thesolvent was evaporated. The crude residue was purified by radialchromatography (2% methanol in dichloromethane, 2 mm silica gel plate)to provide 0.134 g (41%) of a free base of the title compound (R_(f)0.61) as a white foam. The maleate salt was prepared to provide thetitle compound.

-   [α]_(D)=−3.99 (c 0.40, methanol).-   FDMS m/e=414 (M⁺ of free base). C₂₇H₃₀N₂O₂.C₄H₄O₄

analysis: calculated found C 70.31 70.10 H 6.28 6.34 N 5.29 5.19

EXAMPLE 113 Preparation oftrans-(2S)-(−)-1-(4-Indolyioxy)-3-((2-methyl-4-naphth-2-yl)piperidin-1-yl)-2-propanolmaleate.

Scheme IV, Step B: A solution of (S)-(+)4-(oxiranylmethoxyy-1H-indole(0.118 g, 0.62 mmol) and 2-methyl-4-(naphth-2-yl) piperidine (0.141 g,0.61 mmol, trans-Isomer, prepared in example 111) in methanol wasstirred at reflux for 12 h. The mixture was cooled to room temperatureand the solvent was evaporated. The crude residue was purified by radialchromatography (2% methanol in dichloromethane, 2 mm silica gel plate)to provide 0.102 g (39%) of a free base of the title compound (R_(f)0.67) as a white foam. The maleate salt was prepared to provide thetitle compound.

-   [α]_(D)=−9.75 (c 0.41, methanol).-   FDMS m/e=414 (M⁺ of free base).-   C₂₇H₃₀N₂O₂.C₄H₄O₄.3/2H₂O

analysis: calculated found C 67.13 66.85 H 6.17 6.20 N 5.05 5.03

EXAMPLE 114 Preparation oftrans-(2S)-(−)-1-(4-Indolyloxy)-3-((2-methyl-4-naphth-2-yl)piperidin-1-yl)-2-propanolmaleate.

Scheme IV, Step B: A solution of (S)-(+)-4-(oxiranylmethoxy)-1H-indole(0.118 g, 0.62 mmol) and 2-methyl-4-(naphth-2-yl) piperidine (0.141 g,0.61 mmol, trans-isomer, prepared in example 111) in methanol wasstirred at reflux for 12 h. The mixture was cooled to room temperatureand the solvent was evaporated. The crude residue was purified by radialchromatography (2% methanol in dichloromethane, 2 mm silica gel plate)to provide 0.101 g (39%) of the free base of the title compound (R_(f)0.62) as a white foam. The maleate salt is was prepared to provide thetitle compound.

-   [α]_(D)=−8.59 (c 0.46, methanol).-   FDMS m/e=414 (M⁺ of free base).-   C₂₇H₃₀N₂O₂.C₄H₄O₄.3/4H₂O

analysis: calculated found C 68.43 68.46 H 6.58 6.49 N 5.15 5.18

EXAMPLE 115 Preparation of3-(2,2-Dimethyl-4-naphth-2-yl)piperidin-1-yl-4-indolyloxy-2-propanol

Preparation of2,2-dimethyl-4-hydroxy-4-(naphth-2-yl)-1-(t-butoxycarbonyl)-piperidine.

Scheme I, Step A: 2-bromonaphthalene (1.035 g, 5 mmol) was dissolved intetrahydrofuran (20 mL) and cooled to below −65° C. The cooled solutionwas then treated slowly with s-butyllithium (5.9 mL of a 0.84 M solutionin THF, 5 mmol) and the reaction mixture was stirred for 1.5 hours. ThenN—BOC-2,2-dimethyl-4-piperidone (0.745 g, 3.28 mmol, prepared followingthe general procedure described in J. Org. Chem., 56, 2154–2161 (1991))was dissolved in THF and added slowly to the reaction mixture, whilemaintaining the temperature below −65° C. After addition was complete,the dry ice/acetone cooling bath was left in place and the reaction wasallowed to slowly warm to room temperature overnight with stirring. Thereaction mixture was then diluted with ethyl acetate and washed with 1 Nsodium hydroxide, then 1 N HCl, followed by saturated sodium chloride,dried over anhydrous sodium sulfate, filtered and concentrated undervacuum to provide a crude material (1.48 g). The crude material waspurified by column chromatography (chloroform to 0.5%methanol/chloroform gradient, silica gel) to provide the title compound(0.85 g, 73%).

Preparation of 2,2-dimethyl-4-(naphth-2-yl)-1,2,5,6-tetrahydropyridineand 2,2-dimethyl-4-(naphth-2-yl)-1,2,3,6-tetrahydropyridine.

Scheme I, Step B:2,2-Dimethyl-4-hydroxy-4-(naphth-2-yl)-1-(t-butoxycarbonyl)piperidine(200 mg, prepared above) was dissolved in methylene chloride (9 mL) andtreated with trifluoroacetic acid (1 mL). The mixture was stirred for1.5 hours at room temperature and then poured into saturated aqueoussodium bicarbonate solution. The mixture was then extracted withchloroform (3 times). The organic extracts were combined, washed withsaturated sodium chloride, dried over anhydrous sodium sulfate, filteredand concentrated under vacuum to provide the crude mixture of the titlecompounds (131 mg, 99%) which were carried onto the next step withoutseparation.

Preparation of 2,2-dimethyl-4-(naphth-2-yl)piperidine.

Scheme I, Step C:2,2-Dimethyl-4-(naphth-2-yl)-1-(t-butoxycarbonyl)-1,2,5,6-tetrahydropyridineand2,2-dimethyl-4-(naphth-2-yl)-1-(t-butoxycarbonyl)-1,2,3,6-tetrahydropyridine(127 mg, 0.54 mmol) were dissolved in methanol/THF (1/1) and 5%Palladium on carbon (156 mg) was added to the solution. The reactionmixture was placed on a Parr hydrogenation apparatus at 35 psi ofhydrogen. After 2 hours of hydrogenation, an additional amount of 5%palladium on carbon (188 mg) was added and hydrogenation continued foran additional 4 hours. The reaction mixture was then filtered throughCelite and the filtrate was concentrated under vacuum to provide thetitle compound. The crude material was then carried on to the next stepwithout further purification.

Preparation of Final Title Compound.

Scheme IV, Step B: 2,2-dimethyl-4-(naphth-2-yl)piperidine (129 mg, 0.54mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (102 mg, 0.54 mmol) weredissolved in methanol (20 mL) and heated at reflux overnight. Thereaction mixture was then evaporated to dryness and the crude residuewas purified by column chromatography (methylene chloride to 1%methanol/methylene chloride gradient, silica gel) to provide the freebase of the final title compound (92 mg). This material was converted tothe HCl salt by precipitation with one equivalent of saturated HCl indiethyl ether, and then further purified by reverse phase preparativehigh performance liquid chromatography (silica gel, 10% ethyl isacetate/hexanes) to provide the final title compound (30 mg).

EXAMPLE 116 Preparation of1-(t-Butyloxycarbonyl)-2-methyl-4-(3-methylbenzo[b]thiophen-5-yl)-piperidin-4-ol.

Scheme IA, step A: To a solution of 5-bromo-3-methylbenzo[b]thiophene(3.621 g, 15.9 mmol, from preparation 8) in diethyl ether (100 mL) wasadded magnesium (0.775 g, 31.9 mmol) and 1,2-dibromoethane (1.37 mL,15.9 mmol). The mixture was heated at reflux for 4 hours then cooled to20° C. for 18 hours. A solution of1-(t-butyloxycarbonyl)-2-methyl-4-piperidone (3.74 g, 17.5 mmol) intetrahydrofuran (15 mL) was added dropwise to the mixture. The mixturewas stirred for 24 hours, then diluted with saturated ammonium chlorideand extracted with ethyl acetate three times. The residue was purifiedby silica gel chromatography (dichloromethane/5% methanol indichloromethane gradient eluent) to give 4.36 g (76%) of theintermediate title compound as a yellow amorphous solid. FDMS m/e=362(M⁺+1).

Preparation of2-Methyl-4-(3-methylbenzo[b]thiophen-5-yl)-1,2,3,6-tetrahydropyridine.

Scheme IA, step B:1-(t-Butyloxycarbonyl)-2-methyl-4-(3-methylbenzo[b]thiophen-5-yl)-piperidin-4-ol(26.08 g, 72.1 mmol) was suspended in toluene (700 mL) andp-toluenesulphonic acid hydrate (41.17 g, 0.216 mol) was added. Themixture was heated at reflux for 3 hours, then cooled to roomtemperature. The mixture was evaporated and the residue was diluted with2 N sodium hydroxide then extracted 3 times with ethyl acetate. Thecombined organic layers were dried over sodium sulfate, filtered andevaporated to give the title compound as a yellow oil (14.3 g, 81%).FDMS m/e=244 (M⁺+1).

Preparation of 2-Methyl-4-(3-methylbenzo[b]thiophen-5-yl)piperidine.

Scheme IA, step C: To a solution2-Methyl-4-(3-methylbenzo[b]thiophen-5-yl)-1,2,3,6-tetrahydropyridine(4.422 g, 18.2 mmol) in methanol (30 mL) was added 3% palladium onpolyethylenimine/SiO₂ (4.9 g). The mixture was hydrogenated on a PARRshaker at 50° C. and 45 psi for 24 hours. At this time another 6 g of 3%palladium on polyethylenimine/SiO₂ was added and the mixture washydrogenated for 48 hours at 50° C. and 45 psi. The mixture was cooledand then filtered and the catalyst was washed with boiling methanol. Thecombined organic layers were evaporated and the residue was purified bysilica gel chromatography (dichloromethane/5% methanol, 0.35 M ammoniain dichloromethane gradient elution) to give the title compounds as twoyellow oils.

-   Isomer 1 (cis isomer, 1.9 g, 43%). FDMS m/e=246 (M⁺+1).    C₁₅H₁₉NS.0.3H₂O.

analysis: calculated found C 71.84 72.08 H 7.88 7.90 N 5.59 5.71

-   Isomer 2 (trans isomer, 1.5 g, 34%). FDMS m/e=246 (M⁺+1).    C₁₅H₁₉NS.0.2H₂O

analysis: calculated found C 72.36 72.35 H 7.85 7.92 N 5.63 5.83Preparation ofcis-(2S)-(−)-3-(2-Methyl-4-(3-methylbenzo[b]thiophen-5-yl)piperidin-1-yl)-1-(2-methylindol-4-yl)oxy-2-propanolSuccinate.

Scheme IV, step B: A solution ofcis-2-methyl-4-(3-methylbenzo[b]thiophen-5-yl)piperidine (1.869 g, 7.62mmol, isomer 1) and (2S)-4-glycidyloxy-2-methylindole (1.548 g, 7.62mmol) in methanol (30 mL) was heated at reflux for 18 hours and thencooled and evaporated. The residue was purified by silica gelchromatography (dichloromethane/5% methanol, 0.35 M ammonia indichloromethane gradient elution) to give the free bases of the titlecompounds as two yellow amorphous solids. The succinate salts wereprepared to give the title compounds.

-   

Isomer 1 (0.825 g, 24%, free base). FDMS m/e=449 (M⁺+1 of free base).[α]_(D)=−14.06 (c 0.569, methanol). C₂₇H₃₂N₂O₂S.C₄H₆O₄.

analysis: calculated found C 65.70 65.48 H 6.76 6.76 N 4.94 4.94

-   Isomer 2 (0.632 g, 18%, free base). FDMS m/e=449 (M⁺+1 of free    base). [α]_(D)=−7.27 (c 0.55, methanol). C₂₇H₃₂N₂O₂S.C₄H₆O₄.

analysis: calculated found C 65.70 65.30 H 6.76 6.77 N 4.94 4.88Preparation oftrans-(2S)-(−)-3-(2-Methyl-4-(3-methylbenzo[b]thiophen-5-yl)piperidin-1-yl)-1-(2-methylindol-4-yl)oxy-2-propanolSuccinate (Isomers 3 and 4)

Scheme IV, step B: A solution oftrans-2-methyl-4-(3-methylbenzo[b]-thiophen-5-yl)piperidine (3.406 g,13.9 mmol, isomer 2) and (2S)-4-glycidyloxy-2-methylindole (2.821 g,13.9 mmol) in methanol (80 mL) was heated at reflux for 18 hours andthen cooled and evaporated. The residue was purified by silica gelchromatography (dichloromethane/5% methanol, 0.35 M ammonia indichloromethane gradient elution) to give the free bases of the titlecompounds as two yellow amorphous solids. The succinate salts wereprepared to give the title compounds.

-   Isomer 3 (1.918 g, 31%, free base). FDMS m/e=449 (M⁺+1 of free    base). [α]_(D)=−4.02 (c 0.498, methanol). C₂₇H₃₂N₂O₂S.C₄H₆O₄.

analysis: calculated found C 65.70 65.66 H 6.76 6.74 N 4.94 5.00

-   Isomer 4 (1.248 g, 20%, free base). FDMS m/e=449 (M⁺+1 of free    base). [α]_(D)=−12.2 (c 0.492, methanol). C₂₇H₃₂N₂O₂S.C₄H₆O₄.

analysis: calculated found C 65.70 66.01 H 6.76 6.81 N 4.94 4.97Alternative synthesis oftrans-(2S)-(−)-3-(2-Methyl-4-(3-methylbenzo[b]thiophen-5-yl)piperidin-1-yl)-1-(2-methylindol-4-yl)oxy-2-propanol,Isomer 3.Preparation of 5-Bromo-3-methyl-1-trimethylsilylbenzo[b]thiophene.

A solution of 5-bromo-3-methylbenzo[b]thiophene (149.1 g, 0.66 mole,prepared in preparation 8) in THF (1.4 L) under nitrogen was cooled to−78° C. and trimethylsilyl chloride (163 mL, 1.3 mole, 2 eq) was addeddropwise. Lithium diisopropylamide (625 mL, 1.2 mole, 2 eq, 2.0 Msolution in THF, heptane, ethylbenzene) was added and the mixture wasstirred for 4 h. The solution was poured into a mixture of methyltert-butylether and H₂O (3 L each). The layers were separated and theorganic layer was extracted with 1 N HCl (2 L), then H₂O (2 L) and dried(Na₂SO₄). The solvent was removed by rotary evaporation to afford 237.3g of crude product. The crude material was slurried in EtOH (400 mL) toafford 5-bromo-3-methyl-1-trimethylsilylbenzo[b]thiophene as a whitegranular solid (152.7 g, 78%, 3 crops). mp 64–67° C. IR (KBr) 1252,1245, 841 cm⁻¹;

-   ¹H NMR (300 MHz, CDCl₃) δ 7.851 (d, 1, J=1.8 Hz), 7.69 (d, 1, J=8.5    Hz), 7.41 (dd, 1, J=8.5, 1.8 Hz), 2.48 (s, 3,), 0.42 (d, 9, J=3.4    Hz). ¹³C NMR (75 MHz, CDCl₃) δ 143.6, 141.3, 137.9, 132.2, 126.9,    124.4, 123.4, 117.8, 14.4, 0.14. MS (FD) m/z 298 (M+). Anal. Calcd    for C₁₀H₁₅BrSSi: C, 48.16; H, 5.05. Found: C, 48.19; H,4.98.    Preparation of    1-(t-Butyloxycarbonyl)-4-(3-methylbenzo[b]thiophen-5-yl)-piperidin-4-ol.

To a solution of 5-bromo-3-methyl-1-trimethylsilylbenzo[b]thiophene(211.7 g, 707 mmol) in THF (1 L) cooled to −78° C. under nitrogen wasadded n-BuLi (311 mL, 2.5 M solution in hexanes, 778 mmol) dropwise.After 30 min, N-Boc-piperidone (155.1 g, 778 mmol) in THF (816 mL) wasadded. After 2 hr, the mixture was poured into H₂O and methyltert-butylether (2 L each). The layers were separated and the organiclayer was washed with 1 N HCl (2.1 L), then H₂O (2.1 L) and dried(Na₂SO₄). The solvent was removed with a rotary evaporator to afford 348g of crude1-(t-butyloxycarbonyl)-4-(3-methyl-1-trimethylsilylbenzo[b]thiophen-5-yl)-piperidin-4-ol.Hexane (700 mL) was added to the crude product. After stirringovernight, the precipitate was filtered, washed with hexane, and driedin a vacuum oven for 2 hr to give 246.3 g (83%) of1-(t-butyloxycarbonyl)-4-(3-methyl-1-trimethylsilylbenzo[b]thiophen-5-yl)-piperidin-4-olas a white powder. mp 141–145° C. IR (CHCl₃) 3595,1680 cm⁻¹.

-   ¹H NMR (300 MHz, CDCl₃) δ 7.83 (d, 1, J=8.0 Hz), 7.81 (s, 1), 7.43    (dd, 1, J=8.2, 1.8 Hz), 4.06 (br s, 2), 3.28 (t, 2, J=12.2 Hz), 2.51    (s, 3), 2.09 (br s, 2), 1.79 (d, 2, J=12.2 Hz), 1.70 (s, 1), 1.49    (s, 9), 0.40 (s, 9). ¹³C NMR (75 MHz, DMSO) δ 154.2, 145.9, 141.5,    140.3, 139.1, 134.1, 122.2, 121.8, 117.7, 78.6, 70.2, 38.0, 28.3,    14.4, 0.00. MS (FD) m/z 418 (M−1). Anal. Calcd for C₂₂H₃₃NO₃SSi: C,    62.97; H, 7.93; N, 3.34. Found: C, 63.28; H, 8.04; N, 3.44.    Preparation of 4-(3-Methylbenzo[b]thiophen-5-yl)-piperidine    hydrochloride.

To a solution of1-(t-butyloxycarbonyl)-4-(3-methyl-1-trimethylsilylbenzo[b]thiophen-5-yl)-piperidin-4-ol(458 g, 1.09 mol) in CH₂Cl₂ (4.6 L) was added 871 mL (5.46 mol, 5.0equiv) of triethylsilane. The mixture was cooled to −30° C. and 420 mLof trifluoracetic acid (5.45 mol. 5.0 equiv) was added dropwise to thesolution over 35 minutes. The mixture was stirred for 2.5 hours whilegradually warming to 13° C. An additional 420 mL of trifluoroacetic acidwas added over 15 minutes. After warming to room temperature over 3.5hours, ice (6 L), water (5 L), and concentrated aqueous NaOH (628 mL,12.0 mol, 11.0 eq) were added. The layers were separated and the aqueouslayer was extracted with two 1.5 L portions of CH₂Cl₂. The organiclayers were combined, dried (Na₂SO₄), and concentrated under vacuum togive a clear, colorless oil, which was redissolved in 4 L of ether. Thehydrochloride salt was formed by dropwise addition of a solution of HClin EtOAc (245 mL) until the slurry pH measured 2–3. The resulting slurrywas stirred for 2 hours, filtered, rinsed with ether, and driedovernight in a vacuum oven at 45° C. to give 271 g of white crystalline4-(3-methylbenzo[b]thiophen-5-yl)-piperidine hydrochloride (92.8%yield).

-   ¹H NMR (500 MHz, DMSO) δ 2.10–2.20 (m, 2), 2.30 (q, 2), 2.42 (s, 3),    2.93 (m, 1), 3.0–3.10 (m, 2), 7.09 (s, 1), 7.25 (d, 1), 7.57 (s, 1),    7.80 (d, 1); ¹³C NMR (75 MHz, DMSO) δ 13.5, 29.6, 38.9, 43.4, 119.3,    122.7, 122.9, 123.2, 131.5, 137.7, 139.6, 140.9. Anal. Calcd for    C₁₄H₁₈CINS: C, 62.79; H, 6.77; N, 5.23. Found: C, 62.66; H, 6.65; N,    5.24.    Preparation of    N-Chloro-4-(3-methylbenzo[b]thiophen-5-yl)-piperidine.

To 10 g (37 mmol) of 4-(3-methylbenzo[b]thiophen-5-yl)-piperidinehydrochloride was added 160 mL of ether, 34 mL of H₂O and 41 mL (41mmol, 1.1 equiv) of 1 M NaOH. The mixture was stirred until the soliddissolved and the layers were separated using a separatory funnel. Theaqueous layer was extracted with 100 mL of ether and the combinedorganic layers were dried (Na₂SO₄) and evaporated to afford 8.73 g of4-(3-methylbenzo[b]thiophen-5-yl)-piperidine.4-(3-methylbenzo[b]thiophen-5-yl)-piperidine was dissolved in 83 mL ofether and 83 mL of THF, and 4.99 g (37 mmol, 1 equiv) ofN-chlorosuccinimide was added. After stirring overnight, 100 mL ofsaturated aqueous NaHCO₃ was added and the mixture was transferred to aseparatory funnel containing 100 mL of H₂O and 60 mL of ether. Thelayers were separated and the aqueous layer was washed with 10 mL ofether. The combined organic layers were dried (Na₂SO₄) and evaporated toafford 10.1 g (100% yield) ofN-chloro4-(3-methylbenzo[b]thiophen-5-yl)-piperidine; mp57–61.5° C. IR(CHCl₃) 3009, 1602, 1471, 1448cm⁻¹.

-   ¹H NMR (300 MHZ, CDCl₃) δ 7.78 (d, 1, J=8.2 Hz), 7.53 (d, 1, J=1.5    Hz), 7.21 (dd, 1, J=8, 2 Hz), 7.07 (d, 1, J=0.9 Hz), 3.6 (d, 2, J=11    Hz) 3.05 (t, J=12), Hz), 2.85–2.70 (m, 1), 2.43 (d, 3, J=1.2 Hz),    2.20–2.00 (m, 2, CH₂), 1.9 (br d, 2). ¹³C NMR (75 MHz, CDCl₃) δ    141.0, 139.6, 137.5, 131.5, 123.4, 122.9, 122.7, 119.3, 43.6, 40.1,    29.7, 13.5. MS (FD) m/z 266 (M+). Anal. Calcd for C₁₄H₁₆CINS: C,    63.26; H, 6.07; N, 5.27. Found: C, 63.34; H, 6.06; N, 5.30.    Preparation of    trans-2-Methyl-4-(3-methylbenzo[b]-thiophen-5-yl)piperidine.

To 13.9 g (51.9 mmol) ofN-chloro-4-(3-methylbenzo[b]thiophen-5-yl)-piperidine was added 207 mLof THF, 1.0 g (3.8 mmol, 0.073 equiv) of 18-crown-6 and a slurry of10.16 g (assume 85% KOH and 15% H₂O, 156 mmol, 3 equiv) of potassiumhydroxide in 4 mL of H₂O. After stirring for 16 h, the resultingsolution of imine was dried over Na₂SO₄, filtered and the cake rinsedwith 20 mL of THF. A solution of methyllithium in ether (185 mL, 1.5 M,260 mmol, 5 equiv) was cooled to −10° C. and the precooled (5° C.) iminesolution was added over 1 min. After 20 min, the cooling bath wasremoved and the mixture was allowed to stir at ambient temperature.After 2 h, 200 mL of H₂O was added, the layers were separated and theaqueous layer was extracted with ether (200 mL). The combined organiclayers were washed with water (300 mL) and dried (Na₂SO₄). The solventwas evaporated to afford 13.6 g of a viscous oil. The crude product wasdissolved in 80 mL of methanol and 25 mL of THF and 0.55 g (12 mmol) ofNaBH₄ was added. After 2 h, pivalic anyhydride (2.8 g, 12 mmol), wasadded. After 2 h, the methanol was removed by evaporation and themixture was partitioned between 200 mL of 1 N HCl and 100 mL of ether.The layers were separated and the aqueous layer was washed with ether.The aqueous layer was made basic with 5 N NaOH and extracted with ether(2×150 mL). The organic layers were dried and evaporated to afford 8.9 g(63% yield) oftrans-2-methyl-4-(3-methylbenzo[b]-thiophen-5-yl)piperidine as a viscousoil.

Preparation oftrans-(2S,4R)-2-Methyl-4-(3-methylbenzo[b]-thiophen-5-yl)piperidineD-(−)-tartrate.

To a solution of racemictrans-2-methyl-4-(3-methylbenzo[b]-thiophen-5-yl)piperidine (32.7 g,0.13 mol), which had been purifed by filtration through silica gel (2 gsilica gel per g) in 92% recovery, in 3A EtOH (650 mL) at 72° C. wasadded a solution of D(−)-tartaric acid (20.0 g, 0.13 mol, 1.0 equiv) in3A EtOH (450 mL) over 1 hour. The resulting slurry was stirred at 72° C.for 2 hours and then allowed to cool to room temperature over 16 hours.The solid was collected by filtration, rinsed with 3A EtOH and driedbriefly under vacuum at 45° C. The wet cake was slurried in a freshportion of 3A EtOH (1.6 L) at 72° C. for 0.5 hour, cooled to roomtemperature, filtered and rinsed with 3A EtOH. This reslurry wasrepeated 2 more times and the resulting final salt dried overnight undervacuum at 45° C. to give the resolved tartrate salt oftrans-2-methyl-4-(3-methylbenzo[b]-thiophen-5-yl)piperidine (13.1 g, 80%yield of desired isomer, 92% ee).

-   ¹H NMR (300 MHz, DMSO) δ 1.37 (d, 3), 1.73–1.85 (m, 1), 1.85–2.04    (m, 2), 2.04–2.2 (m, 1), 2.38 (s, 3), 2.50 (s, 1H, 3.06–3.30 (m, 3),    4.00 (s, 2), 7.25 (d, 1), 7.34 (s, 1), 7.60 (s, 1), 7.87 (s, 1).    Anal. Calcd for C₁₉H₂₅NO₆S: C, 57.71; H, 6.37; N, 3.54. Found: C,    57.56; H. 6.47; N, 3.56.    Preparation of    trans-(2S)-(−)-3-(2-Methyl-4-(3-methylbenzo[b]thiophen-5-yl)piperidin-1-yl)-1-(2-methylindol-4-yl)oxy-2-propanol    p-toluenesulfonate.

The trans-(2S,4R)-2-methyl-4-(3-methylbenzo[b]-thiophen-5-yl)piperidinetartrate (0.50 g, 1.26 mmol, 1.0 equiv, prepared directly above) wasfree based by addition of EtOAc (10 mL), water (10 mL), and 5N NaOH (1.0mL). The layers were separated and the aqueous layer extracted withEtOAc (10 mL). The combined organic layers were dried (Na₂SO₄) andconcentrated under vacuum to give an oil (0.30 g). This oil wasdissolved in isopropyl alcohol (4.0 mL),(2S)-4-glycidyloxy-2-methylindole (0.2 g, 1.25 mmol, prepared inexample 1) was added, and the mixture heated at 80° C. for 2 hours. Themixture was added to a separatory funnel containing EtOAc (25 mL), water(25 mL), and 1 N NaOH (1 mL). The layers were separated and the aqueouslayer was washed with EtOAc (25 mL). The combined organic layers weredried (Na₂SO₄) and 0.24 g of p-toluenesulfonic acid (1.0 equiv) wasadded. The solution was concentrated, seeded, and heated to generate acrystalline slurry. The slurry was stirred at room temperature for 1hour. The solid was collected by filtration, rinsed with EtOAc, anddried overnight at 45° C. under vacuum to afford the title compound(0.64 g, 82% yield). ¹H NMR (500 MHz, CDCl₃) δ 1.50 (d, 3), 1.90 (d, 1),2.08 (d, 1), 2.27 (s, 3), 2.40 (s, 3), 2.43 (s, 3), 2.59–2.66 (m, 1),2.85 (dt, 1), 3.02–3.17 (m, 2), 3.25–3.3.38 (m, 2), 3.67 (d, 1),4.0–4.15 (m, 2), 4.30 (m, 1), 4.70 (m, 1), 6.20 (s, 1), 6.50 (d, 1),6.93–7.02 (m, 2), 7.15–7.28 (m, 4), 7.60 (s, 1), 7.75 (d, 1), 7.83 (d,1), 8.0 (s, 1), 10.30 (s, 1). ¹³C NMR (75 MHz, DMSO) δ 10.96, 13.28,13.50, 13.56, 15.83, 20.72, 25.95, 30.35, 30.93, 32.92, 33.26, 35.98,45.75, 46.85, 53.71, 54.07, 55.99, 56.49, 64.25, 64.57, 69.83, 69.97,96.45, 100.48, 104.61, 119.06, 119.56, 119.83, 120.58, 122.59, 122.72,122.89, 123.36, 123.67, 125.47, 128.06, 131.48, 131.60, 133.75, 137.53,137.72, 137.81, 139.61, 140.13, 140.34, 145.48, 150.75. Anal. Calcd forC₃₄H₄₀NO₅S₂: C, 65.78; H, 6.49; N, 4.51. Found: C, 65.04; H, 6.29; N,4.36.

Additional Preparation oftrans-(2S)-(−)-3-(2-Methyl-4-(3-methylbenzo[b]thiophen-5-yl)piperidin-1-yl)-1-(2-methylindol-4-yl)oxy-2-propanolSalts from Example 116, Isomer 3 Free Base.

Crudetrans-(2S)-(−)-3-(2-methyl-4-(3-methylbenzo[b]thiophen-5-yl)piperidin-1-yl)-1-(2-methylindol-4-yl)oxy-2-propanol(isomer 3, foam) (2.80 g, 6.3 mmol) was dissolved in isopropyl alcohol(20 mL) at room temperature. The solution was divided into three equalportions, and different acids were added to each portion: 1) p-TsOH(0.40 g, 1.0 equiv) was added directly to the solution; 2)benzenesulfonic acid (0.33 g, 1.0 equiv) was dissolved in 2 mL of EtOAcand added to the solution; 3) methanesulfonic acid (0.135 mL, 1.0 equiv)was mixed with 2 mL of EtOAc and added to the solution. These mixtureswere briefly heated, scraped and stirred overnight at room temperature.Each slurry was filtered, rinsed with EtOAc, and dried overnight at 45°C. under vacuum to give the following corresponding solids:

-   trans-(2S)-(−)-3-(2-methyl-4-(3-methylbenzo[b]thiophen-5-yl)piperidin-1-yl)-1-(2-methylindol-4-yl)oxy-2-propanol    p-toluenesulfonate:

1.17 g, 89% yield, mp 207° C.;

-   trans-(2S)-(−)-3-(2-methyl-4-(3-methylbenzo[b]thiophen-5-yl)piperidin-1-yl)-1-(2-methylindol-4-yl)oxy-2-propanol    benzenesulfonate:

1.04 g, 81.1% yield, mp 185° C.;

-   trans-(2S)-(−)-3-(2-methyl-4-(3-methylbenzo[b]thiophen-5-yl)piperidin-1-yl)-1-(2-methylindol-4-yl)oxy-2-propanol    methanesulfonate:

0.75 g, 66.7% yield, mp 124° C.

EXAMPLE 117 Preparation ofcis-(2S)-1-(4-Indolyloxy)-3-(2-methyl-4-(3-methylbenzo[b]-thiophen-5-yl)piperidin-1-yl)-2-propanoloxalate

Scheme IV, step B: A solution ofcis-2-methyl-4-(3-methylbenzo[b]thiphen-5-yl)piperidine (0.110 g, 0.448mmol, isomer 1) and (2S)-4-glycidyloxy-2-methylindole (0.085 g, 0.448mmol) in methanol (5 mL) was heated at reflux for 18 hours and thencooled and evaporated. The residue was purified by silica gelchromatography (dichloromethane/2% methanol, 0.15 M is ammonia indichloromethane gradient elution) to give the free bases of the titlecompounds as two yellow oils. The oxalate salts were prepared to givethe title compounds.

Isomer 1 (0.058 g, 30%, free base). FDMS m/e=435 (M⁺+1 of free base).

Isomer 2 (0.086 g, 44%, free base). FDMS m/e=435 (M⁺+1 of free base).

Preparation oftrans-(2S)-1-(4-Indolyloxy)-3-(2-methyl-4-(3-methylbenzo[b]-thiophen-5-yl)piperidin-1-yl)-2-propanoloxalate

Scheme IV, step B: A solution oftrans-2-methyl-4-(3-methylbenzo[b]-thiophen-5-yl)piperidine (0.104 g,0.424 mmol, isomer 2) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.080g, 0.424 mmol) in methanol (5 mL) was heated at reflux for 18 hours andthen cooled and evaporated. The residue was purified by silica gelchromatography (dichloromethane/5% methanol, 0.35 M ammonia indichloromethane gradient elution) to give the free bases of the titlecompounds as two yellow oils. The oxalate salts were prepared to givethe title compounds.

Isomer 3 (0.048 g, 26%, free base). FDMS m/e=435 (M⁺+1 of free base).

Isomer 4 (0.070 g, 38%, free base). FDMS m/e=435 (M⁺+1 of free base).

EXAMPLE 118 Preparation of1-(t-Butyloxycarbonyl)-4-(6-methoxynaphth-2-yl)-2-methylpiperidin-4-ol.

Scheme I, step A: To a solution of 2-bromo-6-methoxynaphthalene (13.009g, 54.9 mmol) in tetrahydrofuran (400 mL) at −78° C. was added dropwiset-butyllithium (71.0 mL, 0.121 mol). After 30 minutes at −78° C., asolution of 1-(t-butyloxycarbonyl)-2-methyl-4-piperidone (12.87 g, 60.4mmol) in tetrahydrofuran (50 mL) was added dropwise. The mixture wasstirred at −78° C. for 4 hours and then diluted with saturated ammoniumchloride and extracted 3 times with ethyl acetate. The combined organiclayers were dried over sodium sulfate, filtered and evaporated. Theresidue was purified by silica gel chromatography (dichloromethane/2%methanol in dichloromethane gradient eluent) to give 5.81 g (29%) of thetitle compound as a yellow oil. FDMS m/e=362 (M⁺+1).

Preparation of4-(6-Methoxynaphth-2-yl)-2-methyl-1,2,3,6-tetrahydropyridine.

Scheme I, step B:1-(t-Butyloxycarbonyl)-4-(6-methoxynaphth-2-yl)-2-methylpiperidin-4-ol(5.795 g, 8.79 mmol) was suspended in toluene (100 mL) andp-toluenesulphonic acid hydrate (5.016 g, 26.4 mmol) was added. Themixture was heated at reflux for 2 hours, then cooled to roomtemperature. The mixture was evaporated and the residue was diluted with2 N sodium hydroxide, then extracted 3 times with ethyl acetate. Thecombined organic layers were dried over sodium sulfate, filtered andevaporated to give the title compound as a yellow oil (3.95 g, 100%).FDMS m/e=254 (M⁺+1).

Preparation of 4-(6-Methoxynaphth-2-yl)-2-methylpiperidine.

Scheme I, step C: To a solution4-(6-Methoxynaphth-2-yl)-2-methyl-1,2,3,6-tetrahydropyridine (3.9 g,15.4 mmol) in ethanol (200 mL) and 2,2,2-trifluoroethanol (70 mL) wasadded 10% palladium on carbon (400 mg). The mixture was stirred underone atmosphere of hydrogen for 19 hours. The mixture was filtered andthe catalyst was washed with boiling methanol. The combined organiclayers were evaporated and the residue was purified by silica gelchromatography (dichloromethane/5% methanol, 0.35 M ammonia indichloromethane gradient elution) to give the title compound as twoyellow amorphous solids.

Isomer 1 (cis isomer, 1.97 g, 50%). FDMS m/e=256 (M⁺+1).

Isomer 2 (trans isomer, 1.51 g, 38%). FDMS m/e=256 (M⁺+1).C₁₇H₂₁NO.0.5H₂O.

analysis: calculated found C 77.24 77.40 H 8.39 8.40 N 5.30 5.69Preparation ofcis-(2S)-(−)-3-(4-(6-Methoxynaphth-2-yl)-2-methylpiperidin-1-yl)-1-(2-methylindol-4-yl)oxy-2-propanolsuccinate.

Scheme IV, step B: A solution ofcis-4-(6-methoxynaphth-2-yl)-2-methyl-piperidine (1.569 g, 6.14 mmol,isomer 1) and (2S)-4-glycidyloxy-2-methylindole (1.249 g, 6.14 mmol) inmethanol (30 mL) was heated at reflux for 18 hours and then cooled andevaporated. The residue was purified by silica gel chromatography(dichloromethane/2% methanol, 0.15 M ammonia in dichloromethane gradientelution) to give the free bases of the title compounds as two clearcolorless oils. The succinate salts were prepared to give the titlecompounds.

Isomer 1 (0.801 g, 28%, free base). FDMS m/e=459 (M⁺+1 of free base).[α]_(D)=−18.05 (c 0.554, methanol). C₂₉H₃₄N₂O₃.C₄H₆O₄.

analysis: calculated found C 68.73 68.72 H 6.99 6.93 N 4.86 5.23

Isomer 2 (1.144 g, 41%, free base). FDMS m/e=459 (M⁺+1 of free base).[α]_(D)=−7.27 (c 0.55, methanol).

Preparation oftrans-(2S)-(−)-3-(4-(6-Methoxynaphth-2-yl)-2-methylpiperidin-1-yl)-1-(2-methylindol-4-yl)oxy-2-propanolsuccinate.

Scheme IV, step B: A solution oftrans-4-(6-methoxynaphthyl)2-methylpiperidine (1.494 g, 5.85 mmol,isomer 2) and (2S)-4-glycidyloxy-2-methylindole (1.189 g, 5.85 mmol) inmethanol (30 mL) was heated at reflux for 18 hours and then cooled andevaporated. The residue was purified by silica gel chromatography(dichloromethane/2% methanol, 0.15 M ammonia in dichloromethane gradientelution) to give the free bases of the title compounds as two clearcolorless oils. The succinate salts were prepared to give the titlecompounds.

Isomer 3 (1.089 g, 41%, free base). FDMS m/e=459 (M⁺+1 of free base).[α]_(D)=−8.91 (c 0.449, methanol). C₂₉H₃₄N₂O₃.C₄H₆O₄.

analysis: calculated found C 68.73 68.55 H 6.99 6.64 N 4.86 4.90

Isomer 4 (1.041 g, 39%, free base). FDMS m/e=459 (M⁺+1 of free base).[α]_(D)=−3.64 (c 0.549, methanol). C₂₉H₃₄N₂O₃.C₄H₆O₄.0.5H₂O.

analysis: calculated found C 67.67 67.97 H 7.06 6.90 N 4.78 4.90

EXAMPLE 119 Preparation of(2S)-(−)-3-[(2R,4R)-4-(7-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol

Preparation of 2-Fluorobenzenethioacetaldehyde diethyl acetal.

The title compound was prepared in quantitative crude yield from2-fuorobenzenethiol by essentially following the procedures detailed in(Graham, S. L., et. al. J. Med. Chem. 1989,32, 2548–2554).

Preparation of 7-Fluorobenzo[b]thiophene.

To a biphasic mixture of polyphosphoric acid (PPA; 43.0 g) and 385 mL ofdry chlorobenzene heated to reflux, was added dropwise2-fluorobenzenethioacetaldehyde diethyl acetal (19.1 g, 78.1 mmol) in 60mL of chlorobenzene over a period of 2.5 h. The reaction mixture wascooled to room temperature and the organic layer was decanted off thePPA layer. The PPA layer was cooled to 0° C. and diluted with 400 mL ofH₂O. This aqueous layer was extracted with Et₂O (2×500 mL). The combinedorganic layers were dried over MgSO₄ and concentrated under reducedpressure. The residue was purified by a medium pressure chromatographysystem (silica gel, 100% hexanes) to afford 7-fluorobenzo[b]thiophene asa yellow oil (5.42 g, 46%). FDMS m/e=152 (M⁺).

-   ¹HNMR (CDCl₃) 7.59 (d, J=7.8 Hz, 1H), 7.46 (d, J=5.4 Hz, 1H), 7.36    (dd, J=5.4, 3.9 Hz, 1H), 7.31 (dt, J=7.8, 4.9 Hz, 1H), 7.03 (dd,    J=9.8, 7.8 Hz, 1H).    Preparation of    N-t-Butoxycarbonyl-4-(7-fluorobenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol.

Scheme IA, step A: To a solution of 7-fluorobenzo[b]thiophene (4.00 g,26.3 mmol) in dry THF (130 mL) at −78° C. was added 1.6 M n-BuLi inhexanes (18.1 mL, 28.9 mmol). The solution was stirred at −78° C. for 50min. N-t-Butoxycarbonyl-2-methyl-4-piperidone (5.61 g, 26.3 mmol)dissolved in THF (20 mL) was added via a cannula at −78° C. The reactionmixture was stirred at −78° C. for 2 h. The reaction was then quenchedwith 110 mL of saturated aqueous NH₄Cl solution. The mixture wasextracted with EtOAc (2×400 mL). The combined organic layers were thendried over MgSO₄ and filtered. The filtrate was concentrated andpurified by medium pressure chromatography (15% EtOAc/hexanes) to giveN-t-butoxycarbonyl-4-(7-fluorobenzo[b]thiophen-2-yl)-2-methyl-4-piperidinolas a white foam (5.90 g, 61%). IR (CHCl₃) 3350 (br), 1680 cm⁻¹. IonSpray MS 205 (M−160)⁺; 366 (M+H)⁺; 424 (M+CH₃COO⁻)⁻. C₁₉H₂₄FNO₃S

analysis: calculated found C 62.44 62.14 H 6.62 6.92 N 3.83 3.90Preparation of(±)-cis-4-(7-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, steps B and C: To a solution ofN-t-butoxycarbonyl-4-(7-fluorobenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(5.90 g, 16.1 mmol),in dry CH₂Cl₂ (56 mL) at 0° C. was added 24 mL oftrifluoroacetic acid. The solution was stirred at 0° C. for 1 h. Thereaction was then quenched at room temperature with saturated aqueousNaHCO₃ solution (280 mL). The mixture was extracted with CH₂Cl₂ (2×500mL). The combined organic layers were dried over MgSO₄ and concentratedto yield 3.84 g of crude regioisomeric olefins. To a solution of thecrude olefins (3.84 g) in a 3:1 mixture of ethanol (110 mL) and2,2,2-trifluoroethanol (37 mL) was added 10% Pd/C (4.00 g). The blackslurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 16 h. The black slurry was then filtered over apad of diatomaceous earth and washed with ethanol. The filtrate wasconcentrated, and the residue was purified by medium pressurechromatography [silica gel, 4–5% (3.5 M NH₃ in MeOH)/CH₂Cl₂] to givecis-(±)-4-(7-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine as a brownsolid (1.45 g, 36%). mp 55–57° C. IR (KBr) 3246 cm⁻¹. Ion Spray MS 250(M+H)⁺. C₁₄H₁₆FNS

analysis: calculated found C 67.44 67.76 H 6.47 6.76 N 5.62 5.62Preparation of(±)-trans-4-(7-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, steps B and C: To a solution ofN-t-butoxycarbonyl-4-(7-fluorobenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(5.90 g, 16.1 mmol) in dry CH₂Cl₂ (56 mL) at 0° C. was added 24 mL oftrifluoroacetic acid. The solution was stirred at 0° C. for 1 h. Thereaction was then quenched at room temperature with saturated aqueousNaHCO₃ solution (280 mL). The mixture was extracted with CH₂Cl₂ (2×500mL). The combined organic layers were dried over MgSO₄ and concentratedto yield 3.84 g of crude regioisomeric olefins. To a solution of thecrude olefins (3.84 g) in a 3:1 mixture of ethanol (110 mL) and2,2,2-trifluoroethanol (37 mL) was added 10% Pd/C (4.00 g). The blackslurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 16 h. The black slurry was then filtered over apad of diatomaceous earth and washed with ethanol. The filtrate wasconcentrated, and the residue was purified by medium pressurechromatography [silica gel, 4–5% (3.5 M NH₃ in MeOH)/CH₂Cl₂] to givetrans-(±)-4-(7-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine as abrown solid (0.594 g, 15%). mp 45–47° C. IR (KBr) 3226 cm⁻¹. Ion SprayMS 250 (M+H)⁺. C₁₄H₁₆FNS

analysis: calculated found C 67.44 67.69 H 6.47 6.79 N 5.62 5.66Preparation of Final Title Compound.

Scheme IV, step B: A solution of(±)-cis-4-(7-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.700 g,2.81 mmol) and (2S)-4-glycidyloxy-2-methylindole (0.571 g, 2.81 mmol) inMeOH (35mL) was heated at reflux for 48 h and then cooled andevaporated. The residue was purified by silica gel chromatography [1%(3.5 M NH₃ in MeOH)/CH₂Cl₂] to give the final title compound as anoff-white foam (0.434 g, 34%). The hydrochloride salt was prepared with1 equiv. of HCl in EtOAc. mp (HCl) 135–140° C. IR (CHCl₃) 3474, 3350(br), 1246 cm⁻¹. Ion Spray MS 453 (M+H)⁺; 451 (M−H)⁻ 511 (M+CH₃COO⁻)⁻. []_(D)=−11.43 (c 0.53, MeOH). C₂₆H₂₉FN₂O₂S.HCl.0.5H₂O

analysis: calculated found C 62.70 62.45 H 6.27 6.35 N 5.62 5.46

EXAMPLE 120 Preparation of(2S)-(+)-3-[(2S,4S)-4-(7-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol

Scheme IV, step B: A solution of(±)-cis-4-(7-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.700 g,2.81 mmol) and (2S)4-glycidyloxy-2-methylindole (0.571 g, 2.81 mmol) inMeOH (35mL) was heated at reflux for 48 h and then cooled andevaporated. The residue was purified by silica gel chromatography [1%(3.5 M NH₃ in MeOH)/CH₂Cl₂] to give the title propanol as an off-whitefoam (0.338 g, 27%). The hydrochloride salt was prepared with 1 equiv.of HCl in EtOAc. mp (HCl) 162–166° C. IR (CHCl₃) 3474, 3350 (br), 1246cm⁻¹. Ion Spray MS 453 (M+H)⁺; 451 (M−H)⁻ 511 (M+CH₃COO⁻)⁻. []_(D)=27.07 (c 0.52, MeOH). C₂₆H₂₉FN₂O₂S.HCl

analysis: calculated found C 63.86 63.60 H 6.18 6.11 N 5.73 5.74

EXAMPLE 121 Preparation of(2S)-3-[(2S,4R)-4-(7-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol

Scheme IV, step B: A solution of(±)-trans-4-(7-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.400 g,1.60 mmol) and (2S)-4-glycidyloxy-2-methylindole (0.326 g, 1.60 mmol) inMeOH (20 mL) was heated at reflux for 20 h and then cooled andevaporated. The residue was purified by silica gel chromatography [1–2%(3.5 M NH₃ in MeOH)/CH₂Cl₂] to give the title compound as a white foam(0.292 g, 40%). The hydrochloride salt was prepared with 1 equiv. of HClin EtOAc. mp (HCl) 158–161° C. IR (CHCl₃) 3474, 3350 (br), 1246 cm⁻¹.Ion Spray MS 453 (M+H)⁺; 451 (M−H)⁻; 487 (M+Cl)⁻. [ ]_(D)=0 (c 0.50,MeOH). C₂₆H₂₉FN₂O₂S.HCl

analysis: calculated found C 63.86 64.12 H 6.18 6.14 N 5.73 5.63

EXAMPLE 122 Preparation of(2S)-(+)-3-[(2R,4S)-4-(7-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol

Scheme IV, step B: A solution of(±)-trans-4-(7-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.400 g,1.60 mmol) and (2S)-4-glycidyloxy-2-methylindole (0.326 g, 1.60 mmol) inMeOH (20 mL) was heated at reflux for 20 h and then cooled andevaporated. The residue was purified by silica gel chromatography [1–2%;(3.5 M NH₃ in MeOH)/CH₂Cl₂] to give the title compound as a white foam(0.276 g, 38%). The hydrochloride salt was prepared with 1 equiv. of HClin EtOAc. mp (HCl) 155–158° C. IR (CHCl₃) 3473, 3300 (br), 1245 cm⁻¹.Ion Spray MS 453 (M+H)⁺; 451 (M−H)⁻487 (M+Cl)⁻. [ ]_(D)=17.57. (c 0.57,MeOH). C₂₆H₂₉FN₂O₂S.HCl.0.4H₂O

analysis: calculated found C 62.93 62.57 H 6.26 6.26 N 5.65 5.42

EXAMPLE 123 Preparation of(2S)-(−)-3-[(2R,4R)-4-(7-Fluorobenzo[b]thiophen-2-yl)2-methylpiperidin-1-yl]-1-(1H-indol-4-yl)oxy-2-propanol

Scheme IV, step B: A solution of(±)-cis-4-(7-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.600 g,2.41 mmol) and (S)-4-(oxiranylmethoxy)indole (0.455 g, 2.41 mmol) inMeOH (30 mL) was heated at reflux for 24 h and then cooled andevaporated. The residue was purified by silica gel chromatography [1%(2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the title compound as a white foam(0.341 g, 32%). The hydrochloride salt was prepared with 1 equiv. of HClin EtOAc. mp (HCl) 147–150° C. IR (KBr) 3404, 3300 (br), 1243 cm⁻¹. IonSpray MS 439 (M+H)⁺; 437 (M−H)⁻; 497 (M+CH₃COO⁻)⁻. [ ]_(D)=−11.72 (c0.51, MeOH). C₂₅H₂₇FN₂O₂S.0.1H₂O

analysis: calculated found C 68.19 67.92 H 6.23 6.14 N 6.36 6.36

EXAMPLE 124 Preparation of(2S)-(+)-3-[(2S,4S)-4-(7-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1-H-indol-4-yl)oxy-2-propanol

Scheme IV, step B: A solution of(±)-cis-4-(7-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.600 g,2.41 mmol) and (S)-4-(oxiranylmethoxy)indole (0.455 g, 2.41 mmol) inMeOH (30 mL) was heated at reflux for 24 h and then cooled andevaporated. The residue was purified by silica gel chromatography [1%(2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the title compound as a white foam(0.396 g, 38%). The hydrochloride salt was prepared with 1 equiv. of HClin EtOAc. mp (HCl) 150–153° C. IR (KBr) 3408, 3300 (br), 1242 cm⁻¹. IonSpray MS 439 (M+H)⁺; 437 (M−H)⁻; 497 (M+CH₃COO⁻)⁻. [ ]_(D)=29.20 (c0.55, MeOH). C₂₅H₂₇FN₂O₂S

analysis: calculated found C 68.47 68.08 H 6.21 6.18 N 6.39 6.58

EXAMPLE 125 Preparation of(2S)-3-[(2S,4R)-4-(7-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1-H-indol-4-yl)oxy-2-propanol

Scheme IV, step B: A solution of(±)-trans-4-(7-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.171 g,0.686 mmol) and (S)-4-(oxiranylmethoxy)indole (0.130 g, 0.686 mmol) inMeOH (9 mL) was heated at reflux for 17 h and then cooled andevaporated. The residue was purified by silica gel chromatography [1%(2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the title compound as a white foam(0.122 g, 41%). The hydrochloride salt was prepared with 1 equiv. of HClin EtOAc. IR (KBr) 3406, 3300 (br), 1243 cm⁻¹. Ion Spray MS 439 (M+H)⁺;437 (M−H)⁻. [ ]_(D)=0 (c 0.49, MeOH). C₂₅H₂₇FN₂O₂S

analysis: calculated found C 68.47 68.36 H 6.21 6.34 N 6.39 6.33

EXAMPLE 126 Preparation of(2S)-(+)-3-[(2R,4S)-4-(7-Fluorobenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1-H-indol-4-yl)oxy-2-propanol

Scheme IV, step B: A solution of(±)-trans-4-(7-fluorobenzo[b]thiophen-2-yl)-2-methylpiperidine (0.171 g,0.686 mmol) and (S)-4-(oxiranylmethoxy)indole (0.130 g, 0.686 mmol) inMeOH (9 mL) was heated at reflux for 17 h and then cooled andevaporated. The residue was purified by silica gel chromatography [1%(2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the title compound as a white foam(0.115 g, 38%). The hydrochloride salt was prepared with 1 equiv. of HClin EtOAc. mp (HCl) 146–149° C. IR (KBr) 3405, 3300 (br), 1242 cm⁻¹. IonSpray MS 439 (M+H)⁺; 437 (M−H)⁻; 497 (M+CH₃COO⁻)⁻. [ ]_(D)=10.42 (c0.58, MeOH). C₂₅H₂₇FN₂O₂S

analysis: calculated found C 68.47 68.07 H 6.21 6.55 N 6.39 6.38

EXAMPLE 127 Preparation of(2S)-(−)-3-[(2R,4R)-4-(4-Ethylbenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol

Preparation of ()-N,N-Dimethyl-2-(2-ethylphenyl)-2-hydroxythioacetamide.

A solution of 30.11 g of 1-bromo-2-ethylbenzene in ca. 500 mL of freshlydistilled THF was treated with 112 mL of 1.6 M n-BuLi in hexanes at −78°C. over a period of ca. 3 h. To this was added 15 mL of anhydrous DMF,and the mixture was stirred at −78° C. for 30 min. The cold bath wasremoved, and the reaction was quenched with ca. 300 mL of saturatedaqueous NH₄Cl. The layers were separated, and the organic layer waswashed with ca. 300 mL of brine. The aqueous layers were back extractedwith 2×500 mL of EtOAc. Combined organic layers were dried over MgSO₄,concentrated, and dried under house vacuum to yield 20.89 g (96%) offairly clean crude 2-ethylbenzaldehyde.

To 29.0 mL of diisopropylamide in ca. 500 mL of freshly distilled THF at−70° C. was added 117 mL of 1.6 M n-BuLi in hexanes, and the yellowsolution was stirred at −70° C. for 20 min, for 15 min without the coldbath, then re-cooled to −73° C. To this was added a pre-cooled (−70° C.)mixture of 20.89 g of the crude benzaldehyde and 16 mL ofN,N-dimethylthioformamide in 70 mL of freshly distilled THF via acannula over 15 min. The reddish clear solution was stirred at −75° C.for 45 min, then the cold bath was removed, and the mixture was stirredfor another 30 min. The reaction was quenched with ca. 300 mL ofsaturated aqueous NH₄Cl, and the layers were separated. The aqueouslayer was extracted with 3×500 mL of EtOAc. The organic layers werewashed with ca. 300 mL of brine, combined, dried over MgSO₄, andconcentrated. The residue was crystallized from EtOAc-hexanes to afford25.20 g (73%) of yellowish crystalline solid. IR (CHCl₃) ˜3200 (br),3009, 1529, 1387 cm⁻¹. mp 104–105° C. Ion Spray MS 223.9 (M+H)⁺.C₁₂H₁₇NOS

analysis: calculated found C 64.54 64.70 H 7.67 7.73 N 6.27 6.31Preparation of 4-Ethyl-2-(N,N-dimethylamino)benzo[b]thiophene.

N,N-Dimethyl-2-(2-ethylphenyl)-2-hydroxythioacetamide (25.1 g, 112 mmol)was dissolved in Eaton's reagent (7.5% w/w P₂O₅/MeSO₃H) (330 mL). Thereaction mixture was heated to 80° C. and stirred for 1 h. The reactionmixture was then cooled to room temperature and stirred for anadditional 1.5 h. The reaction was quenched by pouring the reactionmixture slowly into cooled (0° C.) 5.0 N NaOH (1.60 L). The mixture wasextracted with EtOAc (2×1.50 L). The combined organic layers were thendried over MgSO₄ and concentrated to yield the title benzo[b]thiophene(21.66 g, 94% crude yield) as a red oil. EIMS 205 M⁺; 190 (M-15)⁺ (basepeak).

-   ¹HNMR (CDCl₃) 7.42 (d, J=7.8 Hz, 1H), 7.04 (d, J=7.3 Hz, 1H), 6.98    (t, J=7.6 Hz, 1H), 5.98 (s, 1H), 3.01 (s, 6H), 2.82 (q, J=7.8 Hz,    2H), 1.30 (t, J=7.8 Hz, 3H).    Preparation of 4-Etylthianapthen-2-one.

4-ethyl-2-dimethylaminobenzo[b]thiophene (11.10 g, 54.0 mmol) wasdissolved in a 1:1 mixture of THF/1.0 N HCl (380 mL). The biphasicmixture was stirred vigorously and heated at reflux for 3 h 15 min. Thereaction mixture was then cooled to room temperature and the layers wereseparated. The aqueous layer was extracted with EtOAc (2×400 mL). Thecombined organic layers were dried over MgSO₄ and concentrated to give4-ethylthianapthen-2-one (9.63 g, quantitative crude yield) as a darkred solid.

-   ¹HNMR (CDCl₃) 7.19 (t, J=7.8 Hz, 1H), 7.11 (d, J=6.8 Hz, 1H), 7.00    (d, J=7.3 Hz, 1H), 3.82 (s, 2H), 2.51 (q, J=7.8 Hz, 2H), 1.17 (t,    J=7.8 Hz, 3H).    Preparation of 4-Ethylbenzo[b]thiophene.

To a solution of 4-ethylthianapthen-2-one (19.5 g, 110 mmol) in CH₂Cl₂(1.15 L) was added dropwise 1.0 M diisobutylaluminum hydride in toluene(150 mL, 150 mmol) at 0° C. The solution was stirred at 0° C. for 2 h.The reaction was quenched with conc. HCl (700 mL) added dropwise over aperiod of 1.5 h. This mixture was then stirred vigorously for 2 h. Thelayers were separated, and the organic layer was washed with brine(1×500 mL), dried over MgSO₄ and concentrated. The residue was purifiedby medium pressure chromatography (100% hexanes) to give4-ethylbenzo[b]thiophene as a yellow oil (6.37 g, 37%). EIMS 162 M⁺.

-   ¹HNMR (CDCl₃) 7.53 (d, J=7.8 Hz, 1H), 7.09 (t, J=7.8 Hz, 1H), 7.05    (d, J=6.4 Hz, 1H), 6.98 (distorted d, 2H), 2.80 (q, J=7.8 Hz, 2H),    1.15 (t, J=7.8 Hz, 3H).    Preparation of    N-t-Butoxycarbonyl-4-(4-ethylbenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol.

Scheme IA, step A: To a solution of 4-ethylbenzo[b]thiophene (6.37 g,39.2 mmol) in dry THF (200 mL) at −78° C. was added 1.6 M n-BuLi inhexanes (27.0 mL, 43.2 mmol). The solution was stirred at −78° C. for 2h. N-t-Butoxycarbonyl-2-methyl-4-piperidone (6.70 g, 31.4 mmol)dissolved in THF (20 mL) was added via a cannula at −78° C. The reactionmixture was stirred at −78° C. for 3 h. The reaction was then quenchedwith 200 mL of saturated aqueous NH₄Cl solution. The mixture wasextracted with EtOAc (1×200 mL). The combined organic layers were thendried over MgSO₄ and filtered. The filtrate was concentrated andpurified by medium pressure chromatography (20% EtOAc/hexanes) to giveN-t-butoxycarbonyl-4-(4-ethylbenzo[b]thiophen-2-yl)-2-methyl-4-piperidinolas a white foam (6.58 g, 56%). IR (CHCl₃) 3425 (br), 1664, 1692 cm⁻¹.Ion Spray MS 376 (M+H)⁺; 302 (M-73)⁺ (base peak); 434 (M+CH₃COO⁻)⁻.C₂₁H₂₉NO₃S

analysis: calculated found C 67.17 66.94 H 7.78 7.91 N 3.73 3.91Preparation of(±)-cis-4-(4-Ethylbenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, step B and C: To a solution ofN-t-butoxycarbonyl-4-(4-ethylbenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(6.58 g, 17.5 mmol) in dry CH₂Cl₂ (60 mL) at 0° C. was added 25 mL oftrifluoroacetic acid. The solution was stirred at 0° C. for 1.5 h. Thereaction was then quenched at room temperature with saturated aqueousNaHCO₃ solution (260 mL). The mixture was extracted with CH₂Cl₂ (1×300mL). The combined organic layers were dried over MgSO₄ and concentratedto yield 5.90 g of crude regioisomeric olefins. To a solution of thecrude olefins (5.90 g) in a 3:1 mixture of ethanol (135 mL) and2,2,2-trifluoroethanol (40 mL) was added 10% Pd/C (4.50 g). The blackslurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 72 h. The black slurry was then filtered over apad of diatomaceous earth and washed with ethanol. The filtrate wasconcentrated, and the residue was purified by medium pressurechromatography [silica gel, 4% (3.5 M NH₃ in MeOH)/CH₂Cl₂] to givecis-(±)-4-(4-ethylbenzo[b]thiophen-2-yl)-2-methylpiperidine as a yellowsemi-solid (2.37 g, 52%). IR (CHCl₃) 3100 (br) cm⁻¹. Ion Spray MS 260(M+H)⁺. C₁₆H₂₁NS

analysis: calculated found C 74.08 74.06 H 8.16 8.15 N 5.40 5.53Preparation of(±)-trans-4-(4-ethylbenzo[b]thiophen-2-yl)-2-methylpiperidine.

Scheme IA, steps B and C: To a solution ofN-t-butoxycarbonyl-4-(4-ethylbenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(6.58 g, 17.5 mmol) in dry CH₂Cl₂ (60 mL) at 0° C. was added 25 mL oftrifluoroacetic acid. The solution was stirred at 0° C. for 1.5 h. Thereaction was then quenched at room temperature with saturated aqueousNaHCO₃ solution (260 mL). The mixture was extracted with CH₂Cl₂ (1×300mL). The combined organic layers were dried over MgSO₄ and concentratedto yield 5.90 g of crude regioisomeric olefins. To a solution of thecrude olefins (5.90 g) in a 3:1 mixture of ethanol (135 mL) and2,2,2-trifluoroethanol (40 mL) was added 10% Pd/C (4.50 g). The blackslurry was stirred vigorously at room temperature under hydrogen(balloon pressure) for 72 h. The black slurry was then filtered over apad of diatomaceous earth and washed with ethanol. The filtrate wasconcentrated, and the residue was purified by medium pressurechromatography [silica gel, 4% (3.5 M NH₃ in MeOH)/CH₂Cl₂] to givetrans-(±)-4-(4-ethylbenzo[b]thiophen-2-yl)-2-methylpiperidine as ayellow semi-solid (0.855 g, 19%). Ion Spray MS 260 (M+H)⁺. C₁₆H₂₁NS

analysis: calculated found C 74.08 73.86 H 8.16 8.18 N 5.40 5.62Preparation of Final Title Compound.

Scheme IV, step B: A solution of(±)-cis-4-(4-ethylbenzo[b]thiophen-2-yl)-2-methylpiperidine (1.15 g,4.43 mmol) and (2S4-glycidyloxy-2-methylindole (0.900 g, 4.43 mmol) inMeOH (58 mL) was heated at reflux for 24 h and then cooled andevaporated. The residue was purified by silica gel chromatography[0.5–1.5% (3.5 M NH₃ in MeOH)/CH₂Cl₂] to give the final title compoundas an off-white foam (0.568 g, 28%). The hydrochloride salt was preparedwith 1 equiv. of HCl in EtOAc. IR (KBr) 3399, 3350 (br) cm⁻¹. Ion SprayMS 463 (M+H)⁺; 461 (M−H)⁻521 (M+CH₃COO⁻)⁻. [ ]_(D)=−11.90 (c 0.50,MeOH). C₂₈H₃₄N₂O₂S

analysis: calculated found C 72.69 72.63 H 7.41 7.36 N 6.05 6.05

EXAMPLE 128 Preparation of (2S)-(+)-3-[(2S,4S)-4-(4-Ethylbenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol

Scheme IV, step B: A solution of(±)-cis4-(4-ethylbenzo[b]thiophen-2-yl)-2-methylpiperidine (1.15 g, 4.43mmol) and (2S)-4-glycidyloxy-2-methylindole (0.900 g, 4.43 mmol) in MeOH(58 mL) was heated at reflux for 24 h and then cooled and evaporated.The residue was purified by silica gel chromatography [0.5–1.5% (3.5 MNH₃ in MeOH)/CH₂Cl₂] to give the title compound as an off-white foam(0.713 g, 35%). The hydrochloride salt was prepared with 1 equiv. of HClin EtOAc. IR (KBr) 3403, 3300 (br) cm⁻¹. Ion Spray MS 463 (M+H)⁺; 461(M−H)⁻. [ ]_(D)=26.03 (c 0.46, MeOH). C₂₈H₃₄N₂O₂S

analysis: calculated found C 72.69 72.49 H 7.41 7.36 N 6.05 6.04

EXAMPLE 129 Preparation of(2S)-3-[(2S,4R)4-(4-Ethylbenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol

Scheme IV, step B: A solution of(±)-trans-4-(4-ethylbenzo[b]thiophen-2-yl)-2-methylpiperidine (0.511 g,1.97 mmol) and (2S)-4-glycidyloxy-2-methylindole (0.400 g, 1.97 mmol) inMeOH (26 mL) was heated at reflux for 16 h and then cooled andevaporated. The residue was purified by silica gel chromatography [1%(3.5 M NH₃ in MeOH)/CH₂Cl₂] to give the title compound as a white foam(0.233 g, 26%). The hydrochloride salt was prepared with 1 equiv. of HClin EtOAc. IR (KBr) 3399, 3300 (br) cm⁻¹. Ion Spray MS 463 (M+H)⁺; 461(M−H)⁻. [ ]_(D)=0.00 (c 0.57, MeOH). C₂₈H₃₄N₂O₂S.HCl

analysis: calculated found C 67.38 67.54 H 7.07 7.10 N 5.61 5.85

EXAMPLE 130 Preparation of(2S)-(+)-3-[(2R,4S)-4-(4-Ethylbenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol

Scheme IV, step B: A solution of(±)-trans-4-(4-ethylbenzo[b]thiophen-2-yl)-2-methylpiperidine (0.511 g,1.97 mmol) and (2S)-4-glycidyloxy-2-methylindole (0.400 g, 1.97 mmol) inMeOH (26 mL) was heated at reflux for 16 h and then cooled andevaporated. The residue was purified by silica gel chromatography [1%(3.5 M NH₃ in MeOH)/CH₂Cl₂] to give the title compound as a white foam(0.261 g, 29%). The hydrochloride salt was prepared with 1 equiv. of HClin EtOAc. IR (KBr) 3400, 3250 (br) cm⁻¹. mp 153–158° C. Ion Spray MS 463(M+H)⁺; 461 (M−H)⁻. [ ]_(D)=13.22 (c 0.61, MeOH). C₂₈H₃₄N₂O₂S.HCl.0.1H₂O

analysis: calculated found C 67.14 66.80 H 7.08 7.14 N 5.59 5.60

EXAMPLE 131 Preparation of(2S)-(−)-3-[(2R;4R)-4-(4-Ethylbenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-indol-4-yl)oxy-2-propanol

Scheme IV, step B: A solution of(±)-cis-4-(4-ethylbenzo[b]thiophen-2-yl)-2-methylpiperidine (1.17 g,4.52 mmol) and (S)-4-(oxiranylmethoxy)indole (0.856 g, 4.52 mmol) inMeOH (59 mL) was heated at reflux for 18 h and then cooled andevaporated. The residue was purified by silica gel chromatography[0.75–2% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the title compound as awhite foam (0.712 g, 35%). The hydrochloride salt was prepared with 1equiv. of HCl in EtOAc. IR (KBr) 3410, 3400 (br) cm⁻¹. Ion Spray MS 449(M+H)⁺; 447 (M−H)⁻; 507 (M+CH₃COO⁻)⁻. [ ]_(D)=−13.70 (c 0.58, MeOH).C₂₇H₃₂N₂O₂S

analysis: calculated found C 72.29 72.53 H 7.19 7.00 N 6.24 6.05

EXAMPLE 132 Preparation of(2S)-(+)-3-[(2S,4S)-4-(4-Ethylbenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-indol-4-yl)oxy-2-propanol

Scheme IV, step B: A solution of(±)-cis-4-(4-ethylbenzo[b]thiophen-2-yl)-2-methylpiperidine (1.17 g,4.52 mmol) and (S)-4-(oxiranylmethoxy)indole (0.856 g, 4.52 mmol) inMeOH (59 mL) was heated at reflux for 18 h and then cooled andevaporated. The residue was purified by silica gel chromatography[0.75–2% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the title compound as awhite foam (0.498 g, 25%). The hydrochloride salt was prepared with 1equiv. of HCl in EtOAc. IR (KBr) 3416, 3400 (br) cm⁻¹. Ion Spray MS 449(M+H)⁺; 447 (M−H)⁻; 507 (M+CH₃COO⁻)⁻. [ ]_(D)=25.64 (c 0.54, MeOH).C₂₇H₃₂N₂O₂S

analysis: calculated found C 72.29 72.32 H 7.19 7.05 N 6.24 6.16

EXAMPLE 133 Preparation of(2S)-3-[(2S,4R)-4-(4-Ethylbenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-indol-4-yl)oxy-2-propanol

Scheme IV, step B: A solution of(±)-trans-4-(4-ethylbenzo[b]thiophen-2-yl)-2-methylpiperidine (0.462 g,1.78 mmol) and (S)-4-(oxiranylmethoxy)indole (0.337 g, 1.78 mmol) inMeOH (24 mL) was heated at reflux for 18 h and then cooled andevaporated. The residue was purified by silica gel chromatography [1%(2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the title compound as a white foam(0.286 g, 36%). The hydrochloride salt was prepared with 1 equiv. of HClin EtOAc. IR (KBr) 3414, 3400 (br) cm⁻¹. Ion Spray MS 449 (M+H)⁺; 447(M−H)⁻; 483 (M+Cl)⁻; 507 (M+CH₃COO⁻)⁻. [ ]_(D)=0.00 (C 0.57, MeOH).C₂₇H₃₂N₂O₂S.HCl

analysis: calculated found C 66.85 66.52 H 6.86 6.85 N 5.77 5.85

EXAMPLE 134 Preparation of(2S)-(+)-3-[(2R,4S)-4-(4-Ethylbenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-indol-4-yl)oxy-2-propanol

Scheme IV, step B: A solution of(±)-trans-4-(4-ethylbenzo[b]thiophen-2-yl)-2-methylpiperidine (0.462 g,1.78 mmol) and (S)-4-(oxiranylmethoxy)indole (0.337 g, 1.78 mmol) inMeOH (24 mL) was heated at reflux for 18 h and then cooled andevaporated. The residue was purified by silica gel chromatography. [1%(2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the title compound as a white foam(0.223 g, 28%). The hydrochloride salt was prepared with 1 equiv. of HClin EtOAc. IR (KBr) 3416, 3400 (br) cm⁻¹. Ion Spray MS 449 (M+H)⁺; 447(M−H)⁻; 507 (M+CH₃COO⁻)⁻. [ ]_(D)=11.19 (c 0.54, MeOH). C₂₇H₃₂N₂O₂S

analysis: calculated found C 72.29 72.01 H 7.19 7.14 N 6.24 6.13

EXAMPLE 135 Preparation of(2S)-3-[(2S,4R)-4-(4-Hydroxybenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-indol4-yl)oxy-2-propanol

A solution of(2S)-3-[(2S,4R)-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-indol-4-yl)oxy-2-propanol(0.070 g, 0.155 mmol) and sodium thioethoxide (0.039 g, 0.464 mmol) inDMF (2 mL) was heated to 80° C. and stirred for 8 h. Another portion ofsodium thioethoxide (0.039 g, 0.464 mmol) was added and the reaction wasstirred at 80° C. for another 16 h. The reaction was cooled to roomtemperature and quenched with H₂O (9 mL). The mixture was diluted withEtOAc (15 mL) and the layers were separated. The aqueous layer wasextracted with EtOAc (1×30 mL). The combined organic layers were driedover MgSO₄, filtered and concentrated. The residue was purified bysilica gel chromatography [4% (3.5 M NH₃ in MeOH)/CH₂Cl₂] to give thetitle compound as a white solid (0.035 g, 52%). The hydrochloride saltwas prepared with 1 equiv. of HCl in EtOAc. Ion Spray MS 437 (M+H)⁺; 435(M−H)⁻. C₂₅H₂₈N₂O₃S.HCl.0.8H₂O

analysis: calculated found C 61.60 61.34 H 6.33 6.14 N 5.75 5.72

EXAMPLE 136 Preparation of(2S)-(+)-3-[(2R,4S)4-(4-Hydroxybenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-indol-4-yl)oxy-2-propanol

A solution of(2S)-(+)-3-[(2R,4S)-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-indol-4-yl)oxy-2-propanol(0.232 g, 0.515 mmol) and sodium thioethoxide (0.347 g, 4.12 mmol) inDMF (6.6 mL) was heated to 80° C. and stirred for 16 h. The reaction wascooled to room temperature and quenched with H₂O (18 mL). The aqueouslayer was extracted with EtOAc (3×50 mL). The combined organic layerswere dried over MgSO₄, filtered and concentrated. The residue waspurified by silica gel chromatography [4% (3.5 M NH₃ in MeOH)/CH₂Cl₂] togive the title compound as an off-white solid (0.109 g, 49%). Thehydrochloride salt was prepared with 1 equiv. of HCl in EtOAc. IR (KBr)3401, 3350 (br) cm⁻¹. Ion Spray MS 437 (M+H)⁺; 435 (M−H)⁻. [ ]_(D)=11.70(c 0.51, MeOH). C₂₅H₂₈N₂O₃S.0.1H₂O

analysis: calculated found C 68.50 68.25 H 6.48 6.52 N 6.39 6.24

EXAMPLE 137 Preparation of(2S)-(+)-3-[(2R,4R)-4-(4-Hydroxybenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-indol-4-yl)oxy-2-propanol

Preparation ofcis-(±)-4-(4-Hydroxybenzo[b]thiophen-2-yl)-2-methylpiperidine.

A solution of cis-()-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (1.01 g, 3.86mmol) and ethanethiol (2.28 mL, 30.86 mmol) in dichloroethane (38 mL)was treated with AlCl₃ (2.06 g, 15.45 mmol). After stirring for 6 h, theslurry was poured into a solution of saturated aqueous Rochelle's salt(potassium sodium tartrate, 100 mL), MeOH (5 mL), and 2 N NaOH (50 mL),and then extracted with CH₂Cl₂ (3×100 mL). The organic layers were driedover MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography [0 to 20% (2.0 M NH₃in MeOH)/CH₂Cl₂] to givecis-(±)-4-(4-hydroxybenzo[b]thiophen-2-yl)-2-methylpiperidine as anoff-white powder (0.4704 g, 49%).

-   IR (KBr) 3278, 2938, 1571, 1450, 1247,763 cm⁻¹. Ion Spray MS 248.3    (M+H)⁻, 246.3 (M−H)⁻, 493.2 (2M−H)⁻. C₁₄H₁₇NOS

analysis calculated found C 67.97 67.63 H 6.92 7.03 N 5.66 5.70Preparation of Final Title Compound.

Scheme IV, step B: A solution ofcis-(±)-4-(4-hydroxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.218 g,0.884 mmol) and (2S)-4-glycidyloxyindole (0.1672 g, 0.884 mmol) in MeOH(12 mL) was heated at reflux for 19 h and then cooled and evaporated.The residue was purified by silica gel chromatography [2 to 9% (2.0 MNH₃ in MeOH)/CH₂Cl₂] to give the final title compound as a transparentsolid (0.1615 g, 42%). The hydrochloride salt was prepared by dripping 1equivalent of 1.0 M HCl in ether into a solution of the free base in 2mL of EtOAc. mp 164.5° C. (dec). IR (KBr) 3397, 2927, 1276, 1089 cm⁻¹.Ion Spray MS 437.2 (M+H)⁺. [ ]_(D)=27.26 (c 0.587, MeOH).C₂₅H₂₈N₂O₃S.0.2CH₂Cl₂

analysis calculated found C 66.73 67.00 H 6.31 6.43 N 6.18 6.20

EXAMPLE 138 Preparation of(2)-(−)-3-[(2S,4S)-4-(4-Hydroxybenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-indol-4-yl)oxy-2-propanol

Scheme IV, step B: A solution ofcis-(±)-4-(4-hydroxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.218 g,0.884 mmol) and (2S)-4-glycidyloxyindole (0.1672 g, 0.884 mmol) in MeOH(12 mL) was heated at reflux for 19 h and then cooled and evaporated.The residue was purified by silica gel chromatography [2 to 9% (2.0 MNH₃ in MeOH)/CH₂Cl₂] to give the title compound as a transparent solid(0.1579 g, 41%). The hydrochloride salt was prepared by dripping 1equivalent of 1.0 M HCl in ether, into a solution of the free base in 2mL of EtOAc. mp 160.2° C. (dec). IR (KBr) 3407, 2926, 1242, 1086 cm⁻¹.Ion Spray MS 437.2 (M+H)⁺; 435.4 (M−H)⁻. [ ]_(D)=−9.9 (c 0.606, MeOH).C₂₅H₂₈N₂O₃S.0.2CH₂Cl₂

analysis calculated found C 66.73 66.49 H 6.31 6.39 N 6.18 6.15

EXAMPLE 139 Preparation of(2S)-(−)-3-[(2R,4R)-4-(4-Hydroxybenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol

Scheme IV, step B: A solution ofcis-(±)-4-(4-hydroxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.214 g,0.865 mmol) and (2S)-4-glycidyloxy-2-methylindole (0.175 g, 0.865 mmol)in MeOH (40 mL) was heated at reflux for 40 h and then cooled andevaporated. The residue was purified by silica gel chromatography [2 to25% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the title compound as anoff-white solid (0.1589 g, 41%). The hydrochloride salt was prepared bydripping 1 equivalent of 1.0 M HCl in ether into a solution of the freebase in MeOH. mp 145.8° C. (dec). IR (KBr) 3473, 3008, 1246, cm⁻¹. IonSpray MS 451.2 (M+H)⁺; 449.1 (M−H)⁻. [ ]_(D)=−11.98 (c 0.501, MeOH).C₂₆H₃₀N₂O₃S.0.4CH₂Cl₂

analysis calculated found C 65.44 65.59 H 6.41 6.36 N 5.78 6.17

EXAMPLE 140 Preparation of(2S)-(+)-3-[(2S,4S)-4-(4-Hydroxybenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol

Scheme IV, step B: A solution ofcis-(+)-4-(4-hydroxybenzo[b]thiophen-2-yl)-2-methylpiperidine (0.214 g,0.865 mmol) and (2S)4-glycidyloxy-2-methylindole (0.175 g, 0.865 mmol)in MeOH (40 mL) was heated at reflux for 40 h and then cooled andevaporated. The residue was purified by silica gel chromatography [2 to25% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the title compound as anoff-white solid (0.1589 g, 41%). The hydrochloride salt was prepared bydripping 1 equivalent of 1.0 M HCl in ether into a solution of the freebase in MeOH. mp 150.2° C. IR (KBr) 3473, 2936, 1246 cm⁻¹. Ion Spray MS451.2 (M+H)⁺; 449.1 (M−H)⁻. [ ]_(D)=27.72 (c 0.505, MeOH).C₂₆H₃₀N₂O₃S.0.1H₂O.0.2CH₂Cl₂

analysis calculated found C 67.04 66.84 H 6.57 6.52 N 5.97 6.24

EXAMPLE 141

Preparation of(2S)-(+)-3-[(2S,4R)-4-(4-Hydroxybenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-2-methylindol-4-yl)oxy-2-pronanol.

A solution of(2S)-(−)-3-[(2S,4R)-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol(0.2903 g, 0.624 mmol) and sodium ethanethiolate (0.840 g, 9.99 mmol) inDMF (10 mL) was heated at reflux for 16 h and then cooled andevaporated. The residue was diluted with 25 mL of saturated aqueousNaHCO₃ and extracted with CH₂Cl₂ (2×25 mL). The organic layers weredried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography [2 to 12% (2.0 M NH₃in MeOH)/CH₂Cl₂] to give the title compound as an off-white foam (0.0904g, 32%). The hydrochloride salt was prepared by dripping 1 equivalent of1.0 M HCl in ether into a solution of the free base in MeOH (2 mL). IR(KBr) 3472, 2936, 1246 cm⁻¹. Ion Spray MS 449.1 (M−H)⁻. [ ]_(D)=2.47 (c0.809, MeOH). C₂₆H₃₀N₂O₃S.0.4CH₂Cl₂

analysis calculated found C 65.44 65.71 H 6.41 6.52 N 5.78 5.59

EXAMPLE 142 Preparation of(2S)-(+)-3-[(2R,4S)-4-(4-Hydroxybenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-2-methylindol4-yl)oxy-2-propanol

A solution of(2S)-(−)-3-[(2R,4S)-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol(0.300 g, 0.645 mmol) and sodium ethanethiolate (0.650 g, 7.74 mmol) inDMF (10 mL) was heated at reflux for 55 h and then diluted with 50 mL ofbrine and 50 mL H₂O. The solution was then extracted with EtOAc (3×50mL). The organic layers were washed with 50/50 mixture of brine and H₂O(4×75 mL). The organic layers were then dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography [3% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the titlecompound as a yellow solid (0.1071 g, 37%). The hydrochloride salt wasprepared by dripping 1 equivalent of 1.0 M HCl in ether into a solutionof the free base in MeOH (2 mL). mp 131.4° C. IR (KBr) 3473, 3008, 2936,1245 cm⁻¹. Ion Spray MS 451.2 (M+H)⁺; 449.2 (M−H)⁻. [ ]_(D)=12 (c 0.500,MeOH). C₂₆H₃₀N₂O₃S.0.8H₂O

analysis calculated found C 67.16 66.94 H 6.85 6.65 N 6.02 6.09

EXAMPLE 143 Preparation of(2S)-3-[(2S,4R)-4-(7-t-Butyl-4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidin-1-yl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol

Scheme IV, step B: A solution of trans-()-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine (2.03 g, 7.78mmol) and (2S)-4-glycidyloxy-2-methylindole (1.58 g, 7.78 mmol) in MeOH(100 mL) was heated at reflux for 15 h and then cooled and evaporated.The residue was purified by silica gel chromatography [1% (2.0 M NH₃ inMeOH)/CH₂Cl₂]and then by reverse phase chromatography [40% CH₃CN/60%0.01 N HCl]. The fractions collected and concentrated were taken up in30 mL of CH₂Cl₂ and 30 mL 2.0 N NaOH, and then extracted with CH₂Cl₂(3×30 mL). The organic layers were dried over MgSO₄, filtered andconcentrated under reduced pressure to give the title compound (0.0292g, 0.8%). The hydrochloride salt was prepared by dripping 1 equivalentof 1.0 M HCl in ether into a solution of the free base in EtOAc (2 mL).Ion Spray MS 521.2 (M+H)⁺. C₃₁H₄₀N₂O₃S.1.0HCl.0.7H₂O

analysis calculated found C 65.34 65.13 H 7.50 7.33 N 4.92 4.73

EXAMPLE 144 Preparation of(2S)-3-[2,2-Dimethyl-4-(4-methoxybenzo[b]thiophen-2-yl)piperidin-1-yl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol

Preparation of2,2-Dimethyl-4-(4-methoxybenzo[b]thiophen-2-yl)piperidine.

A solution ofcis-(±)-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine in THF (35mL) was cooled to 0° C. (ice-water bath), then treated with NCS (2.26 g,16.94 mol). After stirring 15 minutes, the ice-water bath was removedand the mixture was stirred at room temperature for 45 minutes. Themixture was then concentrated under reduced pressure and diluted withEt₂O (100 mL), saturated aqueous NaHCO₃ (50 mL) and H₂O (50 mL). Themixture was shaken and partitioned in a separatory funnel. The aqueouslayer was separated and extracted once with Et₂O. The combined organiclayers were washed once with H₂O (50 mL), dried over MgSO₄, filtered andconcentrated under reduced pressure to give thecis-(±)-N-chloro-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidineas a yellow oil (4.78 g, 99%).

A solution of the crudecis-(±)-N-chloro-4-(4-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine(2.348 g, 7.93 mmol) in THF (80 mL) was treated with DBU (1.18 mL, 7.93mmol). After stirring 17 h, the DBU salt was filtered off through asintered funnel, rinsed with Et₂O, and the filtrate was concentratedunder reduced pressure to give4-(4-methoxybenzo[b]thiophen-2-yl)-2-methyl-3,4,5,6-tetrahydropyridineas a golden oil (2. 3 g, 99%) that was immediately used in the nextstep.

To a solution of the crude4-(4-methoxybenzo[b]thiophen-2-yl)-2-methyl-3,4,5,6-tetrahydropyridine(2.19 g, 8.44 mmol) in THF (38 mL) cooled to −78° C. in a dryice/acetone bath, was added dropwise BF₃Et₂O (48%) (3.34 mL, 12.6 mmol)via a syringe. After stirring ten minutes, the solution was treated with24.1 mL (33.77 mmol) of 1.4 M MeLi. The mixture was stirred for 16 h,then quenched with 100 mL of saturated aqueous NH₄Cl and 50 mL of H₂O.The mixture was then extracted with CH₂Cl₂ (3×100 mL). The organiclayers were dried over MgSO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography [2.5 to7% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the title compound as an orangeoil (0.713 g, 30%). IR (KBr) 2936, 1571, 1471, 1259, 1049 cm⁻¹. IonSpray MS 276.2 (M+H)⁺. [ ]_(D)=0 (c 0.578, MeOH).C₁₆H₂₁NOS.0.1H₂O0.1CH₂Cl₂

Analysis calculated found C 67.68 0.02 H 7.55 0.18 N 4.90 0.17Preparation of Final Title Compound.

Scheme IV, step B: A solution of2,2-dimethyl-4-(4-methoxybenzo[b]thiophen-2-yl)piperidine (0.352 g, 1.27mmol) and (2S)-4-glycidyloxy-2-methylindole (0.259 g, 1.27 mmol) in MeOH(20 mL) was heated at reflux for 16 h and then cooled and evaporated.The residue was purified by silica gel chromatography [1.5% (2.0 M NH₃in MeOH)/CH₂Cl₂] to give the title compound as a yellow foam (0.2719 g,44%). The hydrochloride salt was prepared by dripping 1 equivalent of1.0 M HCl in ether into a solution of the free base in EtOAc (3 mL). mp142.6° C. IR (KBr) 3473, 3008, 2965,1258, 1247 cm⁻¹. Ion Spray MS 479.2(M+H)⁺; 477.3 (M−H)⁻; 537.4(M+CH₃COO⁻)⁻. [ ]_(D)=0 (c 0.510, MeOH).C₂₈H₃₄N2O₃S.1.0HCl.0.6H₂O

analysis calculated found C 63.78 63.50 H 6.97 6.61 N 5.29 5.32

EXAMPLE 145 Preparation of(2S)-(+)3-[2,2-Dimethyl-4-(4-methoxybenzo[b]thiophen-2-yl)piperidin-1-yl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol

Scheme IV, step B: A solution of2,2-dimethy-4-(4-methoxybenzo[b]thiophen-2-yl)piperidine (0.352 g, 1.27mmol) and (2S)-4-glycidyloxy-2-methylindole (0.259 g, 1.27 mmol) in MeOH(20 mL) was heated at reflux for 16 h and then cooled and evaporated.The residue was purified by silica gel chromatography [1.5% (2.0 M NH₃in MeOH)/CH₂Cl₂] to give the title compound as an orange solid (0.246 g,40%). The hydrochloride salt was prepared by dripping 1 equivalent of1.0 M HCl in ether into a solution of the free base in EtOAc (3 mL). mp99.5° C. IR (KBr) 3473, 3008, 2937, 1258, 1246 cm⁻¹. Ion Spray MS 479.3(M+H)⁺; 477.2 (M−H)⁻; 457.5 (M+CH₃COO⁻)⁻. [ ]_(D)=39.22 (c 0.510, MeOH).C₂₈H₃₄N₂O₃S.0.2CH₂Cl₂

analysis calculated found C 68.34 68.03 H 7.00 6.97 N 5.65 5.86

EXAMPLE 146 Preparation of(2S)-3-[2,2-Dimethyl-4-(4-hydroxybenzo[b]thiophen-2-yl)piperidin-1-yl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol

A solution of(2S)-3-[2,2-dimethyl-4-(4-methoxybenzo[b]thiophen-2-yl)piperidin-1-yl]-1-(1H-2-methylindol4-yl)oxy-2-propanol(0.6452 g, 1.34 mmol) and sodium ethanethiolate (1.81 g, 21.56 mmol) inDMF (22 mL) was heated at reflux for 20 h, and concentrated underreduced pressure The residue was diluted with 100 mL of saturatedaqueous NaHCO₃ and 75 mL of CH₂Cl₂. After separating the layers, theaqueous layer was extracted with CH₂Cl₂ (2×75 mL). Combined organiclayers were then dried over MgSO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography[1 to 4.5% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the title compound as abrown foam (0.3014 g, 48%). The hydrochloride salt was prepared bydripping 1 equivalent of 1.0 M HCl in ether into a solution of the freebase in MeOH (2 mL). mp 172.9° C. IR (KBr) 3591, 3472, 3008, 2931, 1246cm⁻. Ion Spray MS 465.2 (M+H)+; 463.3 (M−H)⁻. [ ]_(D)=0 (c 0.487, MeOH).C₂₇H₃₂N₂O₃S.0.3CH₂Cl₂

analysis calculated found C 66.90 66.86 H 6.70 6.80 N 5.72 5.58

EXAMPLE 147 Preparation of(2S)-(+)-3-[2,2-Dimethyl-4-(4-hydroxybenzo[b]thiophen-2-yl)piperidin-1-yl]-1-(1H-2-methylindol-4-yloxy-2-propanol

A solution of(2S)-3-[2,2-dimethyl-4-(4-methoxybenzo[b]thiophen-2-yl)piperidin-1-yl]-1-(1H-2-methylindol-4-yl)oxy-2-propanol(0.7319 g, 1.52 mmol) and sodium ethanethiolate (2.05 g, 24.4 mmol) inDMF (25 mL) was heated at reflux for 20 h, and concentrated underreduced pressure. The residue was diluted with 75 mL of saturatedaqueous NaHCO₃ and 75 mL of CH₂Cl₂. After separating the layers, theaqueous layer was extracted with CH₂Cl₂ (2×75 mL). Combined organiclayers were then dried over MgSO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography[1 to 10% (2.0 M NH₃ in MeOH)/CH₂Cl₂] to give the title compound as atan solid (0.200 g, 28%). IR (KBr) 3473, 3018, 2933, 1245 cm⁻¹. IonSpray MS 465.2 (M+H)⁺; 463.3 (M−H)⁺. [ ]_(D)=38.86 (c 0.5147, MeOH).C₂₇H₃₂N₂O₃S.0.4CH₂Cl₂

analysis calculated found C 66.00 66.22 H 6.63 6.85 N 5.62 5.59

EXAMPLE 148 Preparation of cis-(2S)-1-(4-(2-Methyl)indolyloxy)-3-(4-(5-benzo[b]thiophenyl)-2-methylpiperidine-1-yl)-2-propanolIsomer 1 Succinate.

Preparation of4-Hydroxy-4-(5-benzo[b]thiophenyl)-2-methyl-1-t-butyloxycarbonyl-piperidine.

To a solution of 5-bromobenzothiophene (prepared according to J. Het.Chem. 1988, 25, 1271) (14.332 g, 67.3 mmol) in diethyl ether (300 mL)was added magnesium (3.27 g, 135 mmol) and 1,2-dibromoethane (5.8 mL,67.3 mmol). The mixture was refluxed for 4 hours then cooled to 20° C.for 18 hours. A solution of 1-t-butyloxycarbonyl-2-methyl-4-piperidone(15.78 g, 73.98 mmol) in tetrahydrofuran (75 mL) was added dropwise tothe mixture. The mixture was stirred for 24 hours then diluted withsaturated ammonium chloride and extracted with ethyl acetate threetimes. The combined organics were dried over sodium sulfate and thenfiltered and evaporated. The residue was purified using silica gelchromatography (dichloromethane/7% methanol in dichloromethane gradienteluent) to give 12.74 g (55%) of the intermediate title compound as ayellow amorphous solid. FDMS m/e=348 (M⁺+1).

Preparation of 4-(5-Benzo[b]thiophenyl)-2-methyl piperidin-3-ene.

4-Hydroxy-4-(5-benzo[b]thiophenyl)-2-methyl-1-t-butyloxycarbonyl-piperidine(12.7 g, 36.5 mmol) was suspended in toluene (300 mL) andp-toluenesulphonic acid hydrate (20.9 g, 0.110 mol) was added. Themixture was refluxed for 3 hours then cooled to room temperature. Themixture was evaporated and the residue was diluted with 2N sodiumhydroxide then extracted 3 times with ethyl acetate. The combinedorganics were dried over sodium sulfate, filtered and evaporated to givethe intermediate title compound as a yellow amorphous solid (6.310 g,75%). FDMS m/e=230 (M⁺+1).

Preparation of 4-(5-Benzo[b]thiophenyl)-2-methyl piperidine.

To a solution of 4-(5-benzo[b]thiophenyl)-2-methyl piperidin-3-ene (6.28g, 27.4 mmol) in methanol (175 mL) was added 3% palladium onpolyethylenimine/SiO₂ (6.25 g). The mixture was hydrogenated on a PARRshaker at 50° C. and 70 psi for 24 hours. At this time another 6 g of 3%palladium on polyethylenimine/SiO₂ was added and the mixture washydrogenated for 48 hours at 50° C. and 65 psi. The mixture was cooledand then filtered and the catalyst was washed with boiling methanol. Thecombined organics were evaporated and the residue was purified usingsilica gel chromatography (dichloromethane/7% methanol, 0.35 M ammoniain dichloromethane gradient elution) to give the intermediate titlecompound as two yellow oils.

Isomer 1 (cis isomer, 1.445 g, 23%). FDMS m/e=232 (M⁺+1).

Isomer 2 (trans isomer, 1.273 g, 20%). FDMS m/e=232 (M⁺+1).

Preparation of Final Title Compound.

A solution cis-4-(5-benzo[b]thiophenyl)-2-methylpiperidine (1.44 g, 6.22mmol, isomer 1) and (S)-(+)-4-(oxiranylmethoxy)-2-methyl-1H-indole (1.26g, 6.22 mmol) in methanol (30 mL) was refluxed for 19 hours and thencooled and evaporated. The residue was purified using silica gelchromatography (dichloromethane/5% methanol, 0.35M ammonia indichloromethane gradient elution) to give two yellow amorphous solids.The succinate salt of isomer 1 was prepared to give the title compound.

Isomer 1 (1.197 g, 44%, free base). FDMS m/e=435 (M⁺+1 of free base).[D]₅₈₉=−11.15 (c=0.538, methanol). C₂₆H₃₀N₂O₂S.C₄H₆O₄.

analysis: calculated found C 65.20 65.44 H 6.57 6.50 N 5.07 5.03

EXAMPLE 149 Preparation ofcis-(2S)-1-(4-(2-Methyl)indolyloxy)-3-(4-(2-naphthyl)-2-methylpiperidine-1-yl)-2-propanolIsomer 1 Oxalate.

A solution cis-4-(2-naphthyl)-2-methyl piperidine (0.191 g, 0.848 mmol,isomer 1) and (S)-(+)-4-(oxiranylmethoxy)-2-methyl-1H-indole (0.172 g,0.848 mmol) in methanol (10 mL) was refluxed for 20 hours and thencooled and evaporated. The residue was purified using silica gelchromatography (dichloromethane/2% methanol, 0.15M ammonia indichloromethane gradient elution) to give two clear colorless oils. Theoxalate salt was prepared of isomer 1 to give the title compound.

Isomer 1 (0.118 g, 33%, free base). FDMS m/e=429 (M⁺+1 of free base).C₂₈H₃₂N₂O₂.C₂H₂O₄.

analysis: calculated found C 69.48 69.61 H 6.61 6.42 N 5.40 5.63Serotonin 1_(A) Receptor Activity

The compounds of the present invention are active at the serotonin 1_(A)receptor, particularly as antagonists and as partial agonists at thatreceptor, and are distinguished by their selectivity. It is now wellunderstood by pharmacologists and physicians that pharmaceuticals whichhave a single physiological activity, or which are much more active inthe desired activity than in their other activities, are much moredesirable for therapy than are compounds which have multiple activitiesat about the same dose.

The 5-HT_(1A) receptor binding potency of the present compounds aremeasured by a modification of the binding assay described by Taylor, etal. (J. Pharmacol. Exp. Ther. 236, 118–125, 1986); and Wong, et al.,Pharm. Biochem. Behav. 46, 173–77 (1993). Membranes for the bindingassay are prepared from male Sprague-Dawley rats (150–250 g). Theanimals are killed by decapitation, and the brains are rapidly chilledand dissected to obtain the hippocampi. Membranes from the hippocampiare either prepared that day, or the hippocampi are stored frozen (−70°C.) until the day of preparation. The membranes are prepared byhomogenizing the tissue in 40 volumes of ice-cold Tris-HCl buffer (50mM, pH 7.4 at 22° C.) using a homogenizer for 15 sec., and thehomogenate is centrifuged at 39800×g for 10 min. The resulting pellet isthen resuspended in the same buffer, and the centrifugation andresuspension process is repeated three additional times to wash themembranes. Between the second and third washes the resuspended membranesare incubated for 10 min. at 37° C. to facilitate the removal ofendogenous ligands. The final pellet is resuspended in 67 mM Tris-HCl,pH 7.4, to a concentration of 2 mg of tissue original wet weight/200 μL.This homogenate is stored frozen (−70° C.) until the day of the bindingassay. Each tube for the binding assay has a final volume of 800 μL andcontains the following: Tris-HCl (50 mM), pargyline (10 μM), CaCl₂ (3mM), [³H]8-OH-DPAT (1.0 nM), appropriate dilutions of the drugs ofinterest, and membrane resuspension equivalent to 2 mg of originaltissue wet weight, for a final pH of 7.4. The assay tubes are incubatedfor either 10 min. or 15 min. at 37° C., and the contents are thenrapidly filtered through GF/B filters (pretreated with 0.5%polyethylenimine), followed by four one-mL washes with ice-cold buffer.The radioactivity trapped by the filters is quantitated by liquidscintillation spectrometry, and specific [³H]8-OH-DPAT binding to the5-HT_(1A) sites is defined as the difference between [³H]8-OH-DPAT boundin the presence and absence of 10 μM 5-HT.

IC₅₀ values, i.e., the concentration required to inhibit 50% of thebinding, are determined from 12-point competition curves using nonlinearregression (SYSTAT, SYSTAT, Inc., Evanston, Ill.). IC₅₀ values areconverted to K_(i) values using the Cheng-Prusoff equation (Biochem.Pharmacol. 22, 3099–3108 (1973).

Additional binding assays of some of the present compounds are carriedout by an assay method which uses a cloned cell line which expresses theserotonin 1_(A) receptor, rather than the hippocampal membranes. Suchcloned cell lines have been described by Fargin, et al., J. Bio. Chem.,264, 14848–14852 (1989), Aune, et al., J. Immunology, 151, 1175–1183(1993), and Raymond, et al., Naunyn-Schmiedeberg's Arch. Pharmacol.,346,127–137 (1992). Results from the cell line assay are substantiallyin agreement with results from the hippocampal membrane assay.

As was reported by R. L. Weinshank, et al., WO93/14201, the 5-HT_(1A)receptor is functionally coupled to a G-protein as measured by theability of serotonin and serotonergic drugs to inhibit forskolinstimulated cAMP production in NIH3T3 cells transfected with the5-HT_(1A) receptor. Adenylate cyclase activity is determined usingstandard techniques. A maximal effect is achieved by serotonin. AnE_(max) is determined by dividing the inhibition of a test compound bythe maximal effect and determining a percent inhibition. (N. Adham, etal., supra,; R. L. Weinshank, et al., Proceedings of the NationalAcademy of Sciences (USA), 89,3630–3634 (1992)), and the referencescited therein.

Measurement of cAMP Formation

Transfected NIH3T3 cells (estimated Bmax from one point competitionstudies=488 fmol/mg of protein) are incubated in DMEM, 5 mMtheophylline, 10 mM HEPES (4-[2-hydroxyethyl]-1-piperazineethanesulfonicacid) and 10 μM pargyline for 20 minutes at 37° C., 5% carbon dioxide.Drug dose-effect curves are then conducted by adding 6 different finalconcentrations of drug, followed immediately by the addition offorskolin (10 mM). Subsequently, the cells are incubated for anadditional 10 minutes at 37° C., 5% carbon dioxide. The medium isaspirated and the reaction is stopped by the addition of 100 mMhydrochloric acid. To demonstrate competitive antagonism, adose-response curve for 5-HT is measured in parallel, using a fixed doseof methiothepin (0.32 mM). The plates are stored at 4° C. for 15 minutesand then centrifuged for 5 minutes at 500×g to pellet cellular debris,and the supernatant is aliquoted and stored at −20° C. before assessmentof cAMP formation by radioimmunoassay (cAMP radioimmunoassay kit;Advanced Magnetics, Cambridge, Mass.). Radioactivity is quantified usinga Packard COBRA Auto Gamma counter, equipped with data reductionsoftware. Representative compounds are tested for 5-HT_(1A) receptorantagonist activity in the cAMP assay.

5HT_(1A) Antagonist, In Vivo Tests

a) 5HT_(1A) Antagonism Subcutaneous Test

Compounds are tested over a range of subcutaneous doses for activity inblocking the 8-OH-DPAT induced behaviors and hypothermia. Lower lipretraction (LLR) and flat body posture (FBP) are recorded in maleSprague Dawley rats (˜250 grams from Harlan Sprague Dawley). Both LLRand FBP are measured on a scale of 0–3 (Wolff et al, 1997). In the LLRbehavioral assay, “0” indicates normal lip position; “1” indicates aslight separation of the lips; “2” indicates that the lips are open withsome teeth visible; “3” indicates that the lips are fully open with allthe front teeth exposed. In the FBP assay, a score of “0” indicatesnormal body posture; “1” indicates that the stomach is on the floor withthe back in its normal rounded position; “2” indicates that the stomachis on the floor with the back straightened and rising from the shouldersto the hips; “3” indicates that the stomach is pressed into the floorand the back is flattened with the shoulders and hips even. Core bodytemperature is recorded by rectal probe inserted 5.0 cm immediatelyafter the behavioral measures. Rats are injected subcutaneous withcompound (at 0, 0.3, 1.0 and 3.0 mg/kg) 35 minutes before scoring andthe 8-OH-DPAT (0.1 mg/kg subcutaneous) is injected 20 minutes beforescoring.

b) 5HT_(1A) Agonist Subcutaneous Test

The compounds are also tested at a high dose of 10 mg/kg subcutaneousalone to see if they induced 5HT_(1A) agonist-like hypothermia.

The efficacy of the compounds of the invention to inhibit the reuptakeof serotonin is determined by a paroxetine binding assay, the usefulnessof which is set out by Wong, et al., Neuropsychopharmacology, 8, 23–33(1993). Synaptosomal preparations from rat cerebral cortex are made fromthe brains of 100–150 g Sprague-Dawley rats which are killed bydecapitation. The cerebral cortex is homogenized in 9 volumes of amedium containing 0.32 M sucrose and μM glucose. The preparations areresuspended after centrifugation by homogenizing in 50 volumes of coldreaction medium (50 μM sodium chloride, 50 μM potassium chloride, pH7.4) and centrifuging at 50,000 g for 10 minutes. The process isrepeated two times with a 10-minute incubation at 37° C. between thesecond and third washes. The resulting pellet is stored at −70° C. untiluse. Binding of ³H-paroxetine to 5-HT uptake sites is carried out in 2ml reaction medium containing the appropriate drug concentration, 0.1 nM³H-paroxetine, and the cerebral cortical membrane (50 μg protein/tube).Samples are incubated at 37° C. for 30 minutes; those containing 1 μMfluoxetine are used to determine nonspecific binding of ³H-paroxetine.After incubation, the tubes are filtered through Whatman GF/B filters,which are soaked in 0.05% polyethylenimine for 1 hour before use, usinga cell harvester by adding about 4 ml cold Tris buffer (pH 7.4),aspirating, and rinsing the tubes three additional times. Filters arethen placed in scintillation vials containing 10 mL scintillation fluid,and the radioactivity is measured by liquid scintillationspectrophotometry.

The pharmacological activities which have been described immediatelyabove provide the mechanistic basis for the pharmaceutical utility ofthe compounds described in this document. A number of pharmaceuticalutilities will be described below.

The activity of the compounds at the serotonin 1_(A) receptor provides amethod of affecting the serotonin 1_(A) receptor which comprisesadministering to a patient in need of such treatment an effective amountof a compound of formula 1. Reasons for the necessity of affecting theserotonin 1_(A) receptor will be described in detail below, but in allcases the effect on the serotonin 1_(A) receptor is brought aboutthrough the compounds' potency as antagonists or partial agonists atthat receptor. A patient in need of a modification of the effects. ofthe 5-HT_(1A) receptor is one having one, or more of the specificconditions and problems to be further described, or a condition orproblem not yet recognized as created by an imbalance or malfunction ofthe 5-HT_(1A) receptor, since research on the central nervous system ispresently ongoing in many fields and newly discovered relationshipsbetween receptors and therapeutic needs are continually beingdiscovered. In all cases, however, it is the compounds' ability toaffect the serotonin 1_(A) receptor which creates their physiological ortherapeutic effects.

Further, the activity of compounds of formula I in the inhibition of thereuptake of serotonin provides a method of inhibiting the reuptake ofserotonin comprising administering to a patient in need of suchtreatment an effective amount of a compound of that formula. Thetreatment of depression with drugs of the class of which fluoxetine isthe leader has become perhaps the greatest medical breakthrough of thepast decade. Numerous other treatment methods carried out by theadministration of the compounds of formula I will be set out in detailbelow.

The unique combination of 5-HT_(1A) receptor activity and serotoninreuptake inhibition possessed by the compounds of the invention afford amethod of providing to a patient both physiological activities with asingle administration of a compound of that formula. As discussed in theBackground section of this document, the value of combining the twoeffects has been discussed in the literature, and it is believed thatthe present compounds are advantageous in that they provide bothphysiological effects in a single drug. It is presently believed thatthe result of administration of a compound of formula I is to providephysiological and therapeutic treatment methods which are typical ofthose provided by presently known serotonin reuptake inhibitors, butwith enhanced efficacy and quicker onset of action.

The activities of compounds of formula I at the 5-HT_(1A) receptor andin reuptake inhibition are of comparable potencies, so an effectiveamount as defined hereinabove for affecting the serotonin 1_(A) receptoror for inhibiting the reuptake of serotonin, is effective for affectingthe serotonin 1_(A) receptor and for inhibiting the reuptake ofserotonin in a patient.

Further discussion of specific therapeutic methods provided by the dualactivity compounds of formula I, and the diseases and conditionsadvantageously treated therewith, are provided below.

The compounds of the present invention are useful for binding, blockingor modulating the serotonin 1_(A) receptor, and for the treatment ofconditions caused by or influenced by defective function of thatreceptor. In particular, the compounds are useful for antagonism at theserotonin 1_(A) receptor, and accordingly, are useful for the treatmentof conditions caused by or affected by excessive activity of thatreceptor.

More particularly, the compounds are useful in the treatment of anxiety,depression, hypertension, cognitive disorders, Alzheimer's disease,psychosis, sleep disorders, gastric motility disorders, sexualdysfunction, brain trauma, memory loss, appetite disorders, bulimia,obesity, substance abuse, obsessive-compulsive disease, panic disorderand migraine.

Depression in its many variations has recently become much more visibleto the general public than it has previously been. It is now recognizedas an extremely damaging disorder, and one that afflicts a surprisinglylarge fraction of the human population. Suicide is the most extremesymptom of depression, but millions of people, not quite so drasticallyafflicted, live in misery and partial or complete uselessness, andafflict their families as well by their affliction. The introduction offluoxetine was a breakthrough in the treatment of depression, anddepressives are now much more likely to be diagnosed and treated thanthey were only a decade ago.

Depression is often associated with other diseases and conditions, orcaused by such other conditions. For example, it is associated withParkinson's disease; with HIV; with Alzheimer's disease; and with abuseof anabolic steroids. Depression may also be associated with abuse ofany substance, or may be associated with behavioral problems resultingfrom or occurring in combination with head injuries, mental retardationor stroke. Depression in all its variations is a preferred target oftreatment with the compounds of the present invention.

Obsessive-compulsive disease appears in a great variety of degrees andsymptoms, generally linked by the victim's uncontrollable urge toperform needless, ritualistic acts. Acts of acquiring, ordering,cleansing and the like, beyond any rational need or rationale, are theoutward characteristic of the disease. A badly afflicted patient may beunable to do anything but carry out the rituals required by the disease.Fluoxetine is approved in the United States and other countries for thetreatment of obsessive-compulsive disease and has been found to beeffective.

Obesity is a frequent condition in the American population. It has beenfound that fluoxetine will enable an obese patient to lose weight, withthe resulting benefit to the circulation and heart condition, as well asgeneral well is being and energy.

Urinary incontinence is classified generally as stress or urgeincontinence, depending on whether its root cause is the inability ofthe sphincter muscles to keep control, or the overactivity of thebladder muscles.

The present treatment methods are useful for treating many otherdiseases, disorders and conditions as well, as set out below. In manycases, the diseases to be mentioned here are classified in theInternational Classification of Diseases, 9th Edition (ICD), or in theDiagnostic and Statistical Manual of Mental Disorders, 3rd VersionRevised, published by the American Psychiatric Association (DSM). Insuch cases, the ICD or DSM code numbers are supplied below for theconvenience of the reader.

-   -   depression, ICD 296.2 & 296.3, DSM 296, 294.80, 293.81, 293.82,        293.83, 310.10, 318.00, 317.00    -   migraine    -   pain, particularly neuropathic pain    -   bulimia, ICD 307.51, DSM 307.51    -   premenstrual syndrome or late luteal phase syndrome, DSM 307.90    -   alcoholism, ICD 305.0, DSM 305.00 & 303.90    -   tobacco abuse, ICD 305.1, DSM 305.10 & 292.00    -   panic disorder, ICD 300.01, DSM 300.01 & 300.21    -   anxiety, ICD 300.02, DSM 300.00    -   post-traumatic syndrome, DSM 309.89    -   memory loss, DSM 294.00    -   dementia of aging, ICD 290    -   social phobia, ICD 300.23, DSM 300.23    -   attention deficit hyperactivity disorder, ICD 314.0    -   disruptive behavior disorders, ICD 312    -   impulse control disorders, ICD 312, DSM 312.39 & 312.34    -   borderline personality disorder, ICD 301.83, DSM 301.83    -   chronic fatigue syndrome    -   premature ejaculation, DSM 3.02.75    -   erectile difficulty, DSM 302.72    -   anorexia nervosa, ICD 307.1, DSM 307.10    -   disorders of sleep, ICD 307.4    -   autism    -   mutism    -   trichotillomania

Anxiety and its frequent concomitant, panic disorder, may beparticularly mentioned in connection with the present compounds. Thesubject is carefully explained by the Diagnostic and Statistical Manualof Mental Disorders, published by the American Psychiatric Association,which classifies anxiety under its category 300.02.

In addition, the unique combination of pharmacological propertiespossessed by the compounds of formula I permit those compounds to beused in a method of simultaneously treating anxiety and depression. Theanxiety portion of the combined syndrome is believed to be attacked bythe 5-HT_(1A) receptor-affecting property of the compounds, and thedepression portion of the condition is believed to be addressed by theserotonin reuptake inhibition property. Thus, administration of aneffective amount, which is determined in an analogous manner asdiscussed hereinabove, of a compound of formula I, will provide a methodof simultaneously treating anxiety and depression.

It is well known that the chronic administration of nicotine results intolerance and, eventually, dependence. The use of tobacco has becomeextremely widespread in all countries, despite the well known adverseeffects of the use of tobacco in all its forms. Thus, it is clear thattobacco use is extremely habit-forming, if not addictive, and that itsuse provides sensations to the user which are pleasant and welcome, eventhough the user may be fully aware of the drastic long term ill effectsof its use.

Rather recently, vigorous campaigns against the use of tobacco havetaken place, and it is now common knowledge that the cessation ofsmoking brings with it numerous unpleasant withdrawal symptoms, whichinclude irritability, anxiety, restlessness, lack of concentration,lightheadedness, insomnia, tremor, increased hunger and weight gain,and, of course, a craving for tobacco.

At the present time, probably the most widely used therapy to assist thecessation of tobacco use is nicotine replacement, by the use of nicotinechewing gum or nicotine-providing transdermal patches. It is widelyknown, however, that nicotine replacement is less effective withouthabit-modifying psychological treatment and training.

Thus, the present method of preventing or alleviating the symptomscaused by withdrawal or partial withdrawal from the use of tobacco or ofnicotine comprises the previously discussed method of affecting theserotonin 1_(A) receptor, in that the treatment method comprises theadministration to a patient an effective amount of a compound of formulaI. The method of the present invention is broadly useful in assistingpersons who want to cease or reduce their use of tobacco or nicotine.Most commonly, the form of tobacco use is smoking, most commonly thesmoking of cigarettes. The present invention is also helpful, however,in assisting in breaking the habit of all types of tobacco smoking, aswell as the use of snuff, chewing tobacco, etc. The present method isalso helpful to those who have replaced, or partially replaced, theiruse of tobacco with the use of nicotine replacement therapy. Thus, suchpatients can be assisted to reduce and even eliminate entirely theirdependence on nicotine in all forms.

A particular benefit of therapy with the present compounds is theelimination or reduction of the weight gain which very often resultsfrom reducing or withdrawing from use of tobacco or nicotine.

It will be understood that the present invention is useful forpreventing or alleviating the withdrawal symptoms which afflict patientswho are trying to eliminate or reduce their use of tobacco or nicotine.The common withdrawal symptoms of such people include, at least,irritability, anxiety, restlessness, lack of concentration, insomnia,nervous tremor, increased hunger and weight gain, light-headedness, andthe craving for tobacco or nicotine. The prevention or alleviation ofsuch symptoms, when they are caused by or occur in conjunction withceasing or reducing the patient's use of tobacco or nicotine, is adesired result of the present invention and an important aspect of it.

The invention is carried out by administering an effective amount of acompound of formula I to a patient who is in need of or carrying out areduction or cessation of tobacco or nicotine use.

As used herein, the term “Patient” refers to a mammal such as a dog,cat, guinea pig, mouse, rat, monkey, or human being. It is understoodthat a human being is the preferred patient.

As used herein, the terms “treating” or “to treat” each mean toalleviate symptoms, eliminate the causation either on a temporary orpermanent basis, or to prevent or slow the appearance of symptoms of thenamed disorder.

As used herein, the term “effective amount” refers to the amount of acompound of formula (I) which is effective, upon single or multiple doseadministration to a patient, in treating the patient suffering from thenamed disorder. The effective amount of compound to be administered, ingeneral, is from about 1 to about 200 mg/day. The daily dose may beadministered in a single bolus, or in divided doses, depending on thejudgment of the physician in charge of the case. A more preferred rangeof doses is, from about 5 to about 100 mg/day; other dosage ranges whichmay be preferred in certain circumstances are from about 10 to about 50mg/day; from about 5 to about 50 mg/day; from about 10 to about 25mg/day; and a particularly preferred range is from about 20 to about 25mg/day.

An effective amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of known techniquesand by observing results obtained under analogous circumstances. Indetermining the effective amount or dose, a number of factors areconsidered by the attending diagnostician, including, but not limitedto: the species of mammal; its size, age, and general health; thespecific disease or disorder involved; the degree of or involvement orthe severity of the disease or disorder; the response of the individualpatient; the particular compound administered; the mode ofadministration; the bioavailability characteristics of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

In effecting treatment of a patient afflicted with a condition, diseaseor disorder described above, a compound of formula (I) can beadministered in any form or mode which makes the compound bioavailablein effective amounts, including oral and parenteral routes. For example,compounds of formula (I) can be administered orally, subcutaneously,intramuscularly, intravenously, transdermally, intranasally, rectally,and the like. Oral administration is generally preferred. One skilled inthe art of preparing formulations can readily select the proper form andmode of administration depending upon the particular characteristics ofthe compound selected, the disease state to be treated, the stage of thedisease, and other relevant circumstances.

It is understood that, while the compounds of formula I individuallyprovide the benefit of the combination of serotonin reuptake inhibitorsand serotonin 1_(A) antagonists, it is entirely possible to administer acompound of formula I in combination with a conventional serotoninreuptake inhibitor in order to obtain still further enhanced results inpotentiating serotonin reuptake inhibition. Examples of representativeserotonin reuptake inhibitors include but are not limited to thefollowing:

Fluoxetine, N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine,is marketed in the hydrochloride salt form, and as the racemic mixtureof its two enantiomers. U.S. Pat. No. 4,314,081 is an early reference onthe compound. Robertson, et al., J. Med. Chem. 31, 1412 (1988), taughtthe separation of the R and S enantiomers of fluoxetine and showed thattheir activity as serotonin uptake inhibitors is similar to each other.In this document, the word “fluoxetine” will be used to mean any acidaddition salt or the free base, and to include either the racemicmixture or either of the R and S enantiomers.

Duloxetine, N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, isusually administered as the hydrochloride salt and as the (+)enantiomer. It was first taught by U.S. Pat. No. 4,956,388, which showsits high potency. The word “duloxetine” will be used here to refer toany acid addition salt or the free base of the molecule.

Venlafaxine is known in the literature, and its method of synthesis andits activity as an inhibitor of serotonin and norepinephrine uptake aretaught by U.S. Pat. No. 4,761,501. Venlafaxine is identified as compoundA in that patent.

Milnacipran (N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide)is taught by U.S. Pat. No. 4,478,836, which prepared milnacipran as itsExample 4. The patent describes its compounds as antidepressants. Moret,et al., Neuropharmacology 24, 1211–19 (1985), describe itspharmacological activities.

Citalopram,1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile,is disclosed in U.S. Pat. No. 4,136,193 as a serotonin reuptakeinhibitor. Its pharmacology was disclosed by Christensen, et al., Eur.J. Pharmacol. 41, 153 (1977), and reports of its clinical effectivenessin depression may be found in Dufour, et al., Int. Clin.Psychopharmacol. 2, 225 (1987), and Timmerman, et al., ibid., 239.

Fluvoxamine, 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanoneO-(2-aminoethyl)oxime, is taught by U.S. Pat. No. 4,085,225. Scientificarticles about the drug have been published by Claassen, et al., Brit.J. Pharmacol. 60, 505 (1977); and De Wilde, et al., J. Affective Disord.4, 249 (1982); and Benfield, et al., Drugs 32, 313 (1986).

Sertraline, 1-(3,4-dichlorophenyl)-4-methylaminotetralin, is disclosedin U.S. Pat. No. 4,536,518.

Paroxetine,trans-(−)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine,may be found in U.S. Pat. Nos. 3,912,743 and 4,007,196. Reports of thedrug's activity are in Lassen, Eur. J. Pharmacol. 47, 351 (1978);Hassan, et al., Brit. J. Clin. Pharmacol. 19, 705 (1985); Laursen, etal., Acta Psychiat. Scand. 71, 249 (1985); and Battegay, et al.,Neuropsychobiology 13, 31 (1985).

All of the U.S. patents which have been mentioned above in connectionwith compounds used in the present invention are incorporated herein byreference.

Fluoxetine or duloxetine are the preferred SRIs in pharmaceuticalcompositions combining a compound of formula I and an SRI, and thecorresponding methods of treatment.

It will be understood by the skilled reader that all of the compoundsused in the present invention are capable of forming salts, and that thesalt forms of pharmaceuticals are commonly used, often because they aremore readily crystallized and purified than are the free bases. In allcases, the use of the pharmaceuticals described above as salts iscontemplated in the description herein, and often is preferred, and thepharmaceutically acceptable salts of all of the compounds are includedin the names of them.

The dosages of the drugs used in the present combination must, in thefinal analysis, be set by the physician in charge of the case, usingknowledge of the drugs, the properties of the drugs in combination asdetermined in clinical trials, and the characteristics of the patient,including diseases other than that for which the physician is treatingthe patient. General outlines of the dosages, and some preferred humandosages, can and will be provided here. Dosage guidelines for some ofthe drugs will first be given separately; in order to create a guidelinefor any desired combination, one would choose the guidelines for each ofthe component drugs.

Fluoxetine: from about 1 to about 80 mg, once/day; preferred, from about10 to about 40 mg once/day; preferred for bulimia andobsessive-compulsive disease, from about 20 to about 80 mg once/day;

Duloxetine: from about 1 to about 30 mg once/day; preferred, from about5 to about 20 mg once/day;

Venlafaxine: from about 10 to about 150 mg once-thrice/day; preferred,from about 25 to about 125 mg thrice/day;

Milnacipran: from about 10 to about 100 mg once-twice/day; preferred,from about 25 to about 50 mg twice/day;

Citalopram: from about 5 to about 50 mg once/day; preferred, from about10 to about 30 mg once/day;

Fluvoxamine: from about 20 to about 500 mg once/day; preferred, fromabout 50 to about 300 mg once/day;

Paroxetine: from about 5 to about 100 mg once/day; preferred, from about50 to about 300 mg once/day.

In more general terms, one would create a combination of the presentinvention by choosing a dosage of SRI according to the spirit of theabove guideline, and choosing a dosage of the compound of formula I inthe ranges taught above.

The adjunctive therapy of the present invention is carried out byadministering a SRI together with a compound of formula I in any mannerwhich provides effective levels of the two compounds in the body at thesame time. All of the compounds concerned are orally available and arenormally administered orally, and so oral administration of theadjunctive combination is preferred. They may be administered together,in a single dosage form, or may be administered separately.

However, oral administration is not the only route or even the onlypreferred route. For example, transdermal administration may be verydesirable for patients who are forgetful or petulant about taking oralmedicine. One of the drugs may be administered by one route, such asoral, and the other may be administered by the trans-dermal,percutaneous, intravenous, intramuscular, intranasal or intrarectalroute, in particular circumstances. The route of administration may bevaried in any way, limited by the physical properties of the drugs andthe convenience of the patient and the caregiver.

It is particularly preferred, however, for the adjunctive combination tobe administered as a single pharmaceutical composition, and sopharmaceutical compositions incorporating both a SRI and a compound offormula I are important embodiments of the present invention. Suchcompositions may take any physical form which is pharmaceuticallyacceptable, but orally usable pharmaceutical compositions areparticularly preferred. Such adjunctive pharmaceutical compositionscontain an effective amount of each of the compounds, which effectiveamount is related to the daily dose of the compounds to be administered.Each adjunctive dosage unit may contain the daily doses of bothcompounds, or may contain a fraction of the daily doses, such asone-third of the doses. Alternatively, each dosage unit may contain theentire dose of one of the compounds, and a fraction of the dose of theother compound. In such case, the patient would daily take one of thecombination dosage units, and one or more units containing only theother compound. The amounts of each drug to be contained in each dosageunit depends on the identity of the drugs chosen for the therapy, andother factors such as the indication for which the adjunctive therapy isbeing given.

As stated above, the benefit of the adjunctive therapy is its ability toaugment the increase in availability of serotonin, norepinephrine anddopamine caused by the SRI compounds, resulting in improved activity intreating the various conditions described below in detail. Theincreasein availability of serotonin is particularly important and is apreferred aspect of the invention. Further, the invention provides amore rapid onset of action than is usually provided by treatment withthe SRI alone.

Pharmaceutical Compositions

The present invention provides pharmaceutical compositions of compoundsof formula I, including the hydrates thereof, comprising, as an activeingredient, a compound of formula I in admixture or otherwise inassociation with one or more pharmaceutically acceptable carriers,diluents or excipients. It is customary to formulate pharmaceuticals foradministration, to provide control of the dosage and stability of theproduct in shipment and storage, and the usual methods of formulationare entirely applicable to the compounds of formula 1. Suchpharmaceutical compositions are valuable and novel because of thepresence of the compounds of formula I therein. Although pharmaceuticalchemists are well aware of many effective ways to formulatepharmaceuticals, which technology is applicable to the presentcompounds, some discussion of the subject will be given here for theconvenience of the reader.

The usual methods of formulation used in pharmaceutical science and theusual types of compositions may be used according to the presentinvention, including tablets, chewable tablets, capsules, solutions,parenteral solutions, intranasal sprays or powders, troches,suppositories, transdermal patches and suspensions. In general,pharmaceutical compositions contain from about 0.5% to about 50% of thecompound of formula (I) in total, depending on the desired dose and thetype of composition to be used. The amount of the compound of formula(I), however, is best defined as the effective amount, that is, theamount of each compound which provides the desired dose to the patientin need of such treatment. The activity of the compounds do not dependon the nature of the composition, so the compositions are chosen andformulated solely for convenience and economy. Any compound may beformulated in any desired form of composition. Some discussion ofdifferent compositions will be provided, followed by some typicalformulations.

Capsules are prepared by mixing the compound with a suitable diluent andfilling the proper amount of the mixture in capsules. The usual diluentsinclude inert powdered substances such as starch of many differentkinds, is powdered cellulose, especially crystalline andmicrocrystalline cellulose, sugars such as fructose, mannitol andsucrose, grain flours and similar edible powders.

Tablets are prepared by direct compression, by wet granulation, or bydry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

A lubricant is necessary in a tablet formulation to prevent the tabletand punches from sticking in the die. The lubricant is chosen from suchslippery solids as talc, magnesium and calcium stearate, stearic acidand hydrogenated vegetable oils.

Tablet disintegrators are substances which swell when wetted to break upthe tablet and release the compound. They include starches, clays,celluloses, algins and gums. More particularly, corn and potatostarches, methylcellulose, agar, bentonite, wood cellulose, powderednatural sponge, cation-exchange resins, alginic acid, guar gum, citruspulp and carboxymethylcellulose, for example, may be used, as well assodium lauryl sulfate.

Enteric formulations are often used to protect an active ingredient fromthe strongly acidic contents of the stomach. Such formulations arecreated by coating a solid dosage form with a film of a polymer which isinsoluble in acidic environments, and soluble in basic environments.Exemplary films are cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate.

Tablets are often coated with sugar as a flavor and sealant, or withfilm-forming protecting agents to modify the dissolution properties ofthe tablet. The compounds may also be formulated as chewable tablets, byusing large amounts of pleasant-tasting substances such as mannitol inthe formulation, as is now well-established practice. Instantlydissolving tablet-like formulations are also now frequently used toassure that the patient consumes the dosage form, and to avoid thedifficulty in swallowing solid objects that bothers some patients.

When it is desired to administer the combination as a suppository, theusual bases may be used. Cocoa butter is a traditional suppository base,which may be modified by addition of waxes to raise its melting pointslightly. Water-miscible suppository bases comprising, particularly,polyethylene glycols of various molecular weights are in wide use, also.

Transdermal patches have become popular recently. Typically theycomprise a resinous composition in which the drugs will dissolve, orpartially dissolve, which is held in contact with the skin by a filmwhich protects the composition. Many patents have appeared in the fieldrecently. Other, more complicated patch compositions are also in use,particularly those having a membrane pierced with pores through whichthe drugs are pumped by osmotic action.

The following typical formulae are provided for the interest andinformation of the pharmaceutical scientist.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg/capsule) Example #1  20 mg Starch, dried 200 mg Magnesiumstearate  10 mg Total 230 mg

As with any group of structurally related compounds which possess aparticular generic utility, certain groups and configurations arepreferred for compounds of formula I or formula Ia.

With respect to substituent R¹, compounds wherein R¹ is hydrogen, F,methyl, ethyl, —C(═O)NR⁸R⁹, or CN are preferred, with hydrogen, methyl,and —C(═O)NH₂ being especially preferred.

With respect to substituent A, compounds wherein A is hydroxy arepreferred. In addition, it is further preferred that when A is hydroxy,it is in the (S)-configuration.

With respect to substituent m, compounds wherein m is 0 or 1 arepreferred.

With respect to substituent n, compounds wherein n is 1 or 2 arepreferred.

With respect to substituents p and q, compounds wherein p and q are bothone are preferred.

With respect to substituent X, compounds wherein X is hydrogen arepreferred.

With respect to substituent R², compounds wherein R² is hydrogen, F, Cl,Br, methyl or methoxy are preferred, with hydrogen being especiallypreferred.

With respect to substituent R³, compounds wherein R³ is hydrogen,methyl, ethyl or propyl are preferred with hydrogen and methyl beingespecially preferred.

With respect to substituent R⁴, compounds wherein R⁴ is hydrogen,methyl, ethyl or propyl are preferred, with hydrogen and methyl beingespecially preferred.

With respect to substituent R⁵, compounds wherein R⁵ is hydrogen, F, Cl,Br, I OH, C₁–C₆ alkyl, C₁–C₆ alkoxy, halo(C₁–C₆) alkyl, phenyl,substituted phenyl, C(═O)NR₈R₉, NO₂, NH₂, and CN are preferred, withhydrogen, F, Cl, Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy,propoxy and isopropoxy being especially preferred.

With respect to substituent R⁶, compounds wherein R⁶ is hydrogen, F, Cl,Br, I OH, C₁–C₆ alkyl, C₁–C₆ alkoxy, halo(C₁–C₆) alkyl, phenyl,substituted phenyl, C(═O)NR₈R₉, NO₂, NH₂, and CN are preferred, withhydrogen, F, Cl, Br, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy,propoxy and isopropoxy being especially preferred.

With respect to substituent R⁷, compounds wherein R⁷ is hydrogen, F, Cl,Br, methyl, ethyl, propyl, isopropyl or butyl are preferred, withmethyl, ethyl, and propyl being especially preferred.

With respect to substituent R⁸, compounds wherein R⁸ is hydrogen,methyl, ethyl, propyl, isopropyl or butyl are preferred.

With respect to substituent R⁹, compounds wherein R⁹ is hydrogen,methyl, ethyl, propyl, isopropyl or butyl are preferred.

With respect to the piperidine portion of formula I, compounds with thefollowing substitutions are preferred:

With respect substituent B, compounds with the following substitutionsare preferred:

More specifically, as shown in Table I, the following substituentsrepresented by B are especially preferred:

TABLE I Substituent B a

b

c

d

e

f

g

h

i

j

k

l

m

n

o

p

q

r

s

t

u

v

w

x

y

z

aa

bb

cc

dd

ee

ff

gg

hh

ii

jj

kk

ll

mm

nn

oo

pp

qq

rr

tt

uu

vv

ww

xx

In addition, compounds of formula Ia′

wherein R⁵ and R⁶are each independently hydrogen or C₁–C₄ alkyl, withthe, proviso that at least one of R⁵ and R⁶ are other than hydrogen aremost especially preferred.

1. A compound of the formula:

wherein A is hydrogen or OH: B is selected from the group consisting of:

represents a single or a double bond; X is hydrogen, OH or C₁–C₆ alkoxywhen

represents a single bond in the piperidine ring, and X is nothing when

represents a double bond piperidine ring; R¹ is hydrogen, F, C₁–C₂₀alkyl, —C(═O)NR⁸R⁹, or CN; R² is hydrogen, F, Cl, Br, I, OH, C₁–C₆ alkylor C₁–C₆ alkoxy; R³ and R⁴ are each independently hydrogen or C₁–C₄alkyl; R⁵ and R⁶ are each independently hydrogen, F, Cl, Br, I, OH,C₁–C₆ alkyl, C₁–C₆alkoxy, halo(C₁–C₆)alkyl, phenyl, —C(═O)NR⁸R⁹, NO₂,NH₂, CN, or phenyl substituted with from 1 to 3 substituents selectedfrom the group consisting of F, Cl, Br, I, OH, C₁–C₆ alkyl, C₁–C₆alkoxy, halo(C₁–C₆)alkyl, NO₂, NH₂, CN, and phenyl; R⁷ is hydrogen, F,Cl, Br, I, OH, C₁–C₆ alkyl or (C₁–C₆ alkyl)NR⁸R⁹; R⁸ and R⁹ are eachindependently hydrogen or C₁–C₁₀ alkyl; m is 0, 1, or 2; n is 0, 1, or2; p is 0, 1, 2, 3 or 4; and q is 0, 1, 2 or 3; or a pharmaceuticallyacceptable salt thereof; with the proviso that if both R³ and R⁴represent hydrogen, then R¹ is F, C₁–C₂₀ alkyl, —C(═O)NR⁸R⁹, or CN.
 2. Acompound of the formula:

wherein B is selected from the group consisting of:

R¹ is hydrogen, F, C₁–C₂₀ alkyl, —C(═O)NR⁸R⁹, or CN; R² is hydrogen, F,Cl, Br, I, OH, C₁–C₆ alkyl or C₁–C₆ alkoxy; R³ and R⁴ are eachindependently hydrogen or C₁–C₄ alkyl; R⁵ and R⁶ are each independentlyhydrogen, F, Cl, Br, I, OH, C₁–C₆ alkyl, C₁–C₆ alkoxy, halo(C₁–C₆)alkyl,phenyl, —C(═O)NR⁸R⁹, NO₂, NH₂, CN, or phenyl substituted with from 1 to3 substituents selected from the group consisting of F, Cl, Br, I, OH,C₁–C₆ alkyl, C₁–C₆ alkoxy, halo(C₁–C₆)alkyl, NO₂, NH₂, CN, and phenyl;R⁷ is hydrogen, F, Cl, Br, I, OH, C₁–C₆ alkyl or (C₁–C₆ alkyl)NR⁸R⁹; R⁸and R⁹ are each independently hydrogen or C₁–C₁₀ alkyl; m is 0, 1, or 2;and n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof; withthe proviso that if both R³ and R⁴represent hydrogen, then R¹ is F,C₁–C₂₀ alkyl, —C(═O)NR⁸R⁹, or CN.
 3. A compound according to claim 2wherein R² is hydrogen.
 4. A compound according to claim 3 wherein R¹ ishydrogen, methyl, or —C(═O)NH₂.
 5. A compound according to claim 2wherein R¹ is hydrogen or methyl.
 6. A compound according to claim 2wherein m is 0 and n is
 1. 7. A compound according to claim 2 wherein R³is hydrogen and R⁴ is methyl.
 8. A compound according to claim 2 whereinB is:


9. A compound according to claim 2 wherein R⁶ and R⁷ are hydrogen.
 10. Acompound according to claim 2 wherein B is:


11. A compound according to claim 10 wherein R⁶ and R⁷ are hydrogen, andR⁵ is methyl, methoxy, F, or Cl.
 12. A method of treating depressioncomprising administering to a patient in need thereof an effectiveamount of a compound of formula:

wherein A is hydrogen or OH: B is selected from the group consisting of:

represents a single or a double bond; X is hydrogen, OH or C₁–C₆ alkoxywhen

represents a single bond in the piperidine ring, and X is nothing when

represents a double bond piperidine ring; R¹ is hydrogen, F, C₁–C₂₀alkyl, —C(═O)NR⁸R⁹, or CN; R² is hydrogen, F, Cl, Br, I, OH, C₁–C₆ alkylor C₁–C₆ alkoxy; R³ and R⁴ are each independently hydrogen or C₁–C₄alkyl; R⁵ and R⁶ are each independently hydrogen, F, Cl, Br, I, OH,C₁–C₆ alkyl, C₁–C₆ alkoxy, halo(C₁–C₆)alkyl, phenyl, —C(═O)NR⁸R⁹, NO₂,NH₂, CN, or phenyl substituted with from 1 to 3 substituents selectedfrom the group consisting of F, Cl, Br, I, OH, C₁–C₆ alkyl, C₁–C₆alkoxy, halo(C₁–C₆)alkyl, NO₂, NH₂, CN, and phenyl; R⁷ is hydrogen, F,Cl, Br, I, OH, C₁–C₆ alkyl or (C₁–C₆ alkyl)NR⁸R⁹; R⁸ and R⁹ are eachindependently hydrogen or C₁–C₁₀ alkyl; m is 0, 1, or 2; n is 0, 1, or2; p is 0, 1, 2, 3 or 4; and q is 0, 1, 2 or 3; or a pharmaceuticallyacceptable salt thereof; with the proviso that if both R³ and R⁴represent hydrogen, then R¹ is F, C₁–C₂₀ alkyl, —C(═O)NR⁸R⁹, or CN. 13.A pharmaceutical composition comprising an effective amount of acompound according to claim 1 in combination with a pharmaceuticallyacceptable carrier, diluent or excipient.
 14. A compound which istrans-(2S,4R)-2-methyl-4-(3-methylbenzo[b]-thiophen-5-yl)piperidineD-(−)-tartrate.
 15. A compound which istrans-(2S,4R)-2-methyl-4-(3-methylbenzo[b]-thiophen-5-yl)piperidine. 16.A compound which iscis-(2S)-(−)-3-(2-Methyl-4-(3-methylbenzo[b]thiophen-5-yl)piperidin-1-yl)-1-(2-methylindol-4-yl)oxy-2-propanolsuccinate.
 17. A compound which iscis-(2S)-(−)-3-(2-Methyl-4-(3-methylbenzo[b]thiophen-5-yl)piperidin-1-yl)-1-(2-methylindol-4-yl)oxy-2-propanol.18. A compound which iscis-(2S)-(−)-3-(2-Methyl-4-(3-methylbenzo[b]thiophen-5-yl)piperidin-1-yl)-1-(2-methylindol-4-yl)oxy-2-propanolsuccinate.
 19. A compound which iscis-(2S)-(−)-3-(2-Methyl-4-(3-methylbenzo[b]thiophen-5-yl)piperidin-1-yl)-1-(2-methylindol-4-yl)oxy-2-propanol.